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Review

MLIP and Its Potential Influence on Key Oncogenic Pathways

by
Mahmoud N. Hamwi
1,
Engy Elsayed
1,
Hanan Dabash
2,
Amani Abuawad
2,
Noor A. Aweer
1,
Faissal Al Zeir
1,
Shona Pedersen
1,
Layla Al-Mansoori
3,* and
Patrick G. Burgon
2,*
1
College of Medicine, Qatar University, Doha P.O. Box 0974, Qatar
2
Department of Chemistry and Earth Sciences, College of Arts and Sciences, Qatar University, Doha P.O. Box 2713, Qatar
3
Biomedical Research Centre, Qatar University, Doha P.O. Box 2713, Qatar
*
Authors to whom correspondence should be addressed.
Cells 2024, 13(13), 1109; https://doi.org/10.3390/cells13131109
Submission received: 26 January 2024 / Revised: 27 May 2024 / Accepted: 19 June 2024 / Published: 26 June 2024
(This article belongs to the Section Cell Signaling)
Browse Figures
Versions Notes

Abstract

:
Muscle-enriched A-type lamin-interacting protein (MLIP) is an emerging protein involved in cellular homeostasis and stress adaptation. Eukaryotic cells regulate various cellular processes, including metabolism, DNA repair, and cell cycle progression, to maintain cellular homeostasis. Disruptions in this homeostasis can lead to diseases such as cancer, characterized by uncontrolled cell growth and division. This review aims to explore for the first time the unique role MLIP may play in cancer development and progression, given its interactions with the PI3K/Akt/mTOR pathway, p53, MAPK9, and FOXO transcription factors, all critical regulators of cellular homeostasis and tumor suppression. We discuss the current understanding of MLIP’s involvement in pro-survival pathways and its potential implications in cancer cells’ metabolic remodeling and dysregulated homeostasis. Additionally, we examine the potential of MLIP as a novel therapeutic target for cancer treatment. This review aims to shed light on MLIP’s potential impact on cancer biology and contribute to developing innovative therapeutic strategies.

1. Introduction

Eukaryotic cells maintain cellular homeostasis through an extensive array of sensory mechanisms to respond and adapt to both intrinsic and extrinsic stimuli and insults. This involves the regulation of various cellular processes, including metabolism, DNA repair, and cell cycle progression. Disruptions to cellular homeostasis can lead to the development of various diseases, including cancer. Cancer is a devasting disease with metabolic remodeling and dysregulated homeostasis as distinctive features [1] and is characterized by uncontrolled cell growth and division, leading to the formation of tumors [2]. This process is the result of a disruption in the delicate balance between cell proliferation and cell death [3], which is normally maintained by cellular homeostasis. Several signaling molecules and pathways have been identified as pro-oncogenic and have therefore been targeted for the therapeutic treatment of cancer [4].
The integrated actions of the tumor suppressors p53 (p53), FOXO, and the PI3K/Akt/mTOR pathway enable cells to respond to a wide range of stresses, including oxidative stress, nutrient deprivation, and DNA damage. This integrated stress response is crucial for maintaining cellular and organismal homeostasis. In cancer cells, however, mutations or changes in the genes encoding proteins in this pathway can cause hyperactivation, resulting in uncontrolled cell growth and resistance to apoptosis (programmed cell death). For example, the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt)/mammalian target of rapamycin (mTOR) pathway is tightly regulated in normal cells, ensuring a balance between cell growth and death. However, p53 and forkhead box O family (FOXO), downstream of the PI3K/Akt/mTOR pathway, respectively, are critical integrators of genomic and metabolic stresses [5,6,7,8]. Both p53 and FOXO are stress-activated transcription factors that promote an adaptive pro-survival response to insult [9,10,11]. Specifically, p53 stimulates DNA repair in response to DNA damage [12,13] and FOXO regulates metabolic remodeling to maintain metabolic homeostasis [14,15,16].
Cancer metabolism modifies cellular metabolic pathways to facilitate rapid cell growth and proliferation [17,18,19]. Cancer cells undergo metabolic reprogramming to meet the high energy and biosynthetic demands associated with their fast growth. This reprogramming promotes glycolysis at the expense of oxidative phosphorylation, a phenomenon known as the “Warburg effect”, which occurs even in the presence of oxygen. The “Warburg effect” is the preference of cancer cells to utilize aerobic glycolysis instead of oxidative phosphorylation for energy generation [20,21]. Tumor cells derive advantages from this alteration in metabolism. Initially, glycolysis generates energy at a quicker rate compared to oxidative phosphorylation, although producing a lower amount of ATP. Additionally, glycolysis generates intermediary compounds that are crucial for the synthesis of nucleotides, amino acids, and lipids, all of which play vital roles in the growth and multiplication of cells. Furthermore, cancer cells reduce the production of reactive oxygen species (ROS) and mitigate oxidative stress and apoptosis by minimizing mitochondrial respiration. P53, the PI3K/Akt/mTOR pathway and the FOXO transcription factor have all been implicated in the metabolic remodeling that cancer cells undergo during tumorigenesis [20,22,23,24,25].
Muscle enriched A-type lamin-interacting protein (MLIP) is a novel protein of unknown structure and function that is required for the proper cardiac and skeletal muscle adaptation to stress [26,27,28,29,30,31]. MLIP is a crucial mediator of cardiac adaptation through its interaction with the Akt/mTOR pro-survival pathway [28], FOXO1 [31] and p53 [28]. A detailed comparative pathway analysis based on global gene expression differences between normal and MLIP-deficient hearts has now revealed MLIP as a modulator of both p53 and FOXO activity. Given MLIP’s interactions with the PI3K/Akt pathway, p53, and FOXO [28,32], this review explores the roles MLIP may play in tumor formation and progression and the potential of MLIP as a new therapeutic target. The focus of this review is to explore the relationship of MLIP with well characterized factors that are associated with the development and progression of cancer.

2. MLIP Discovery and Cellular Role

The discovery of muscle-enriched A-type lamin-interacting protein (MLIP) [27] marks a significant advancement in understanding the molecular intricacies associated with laminopathies—degenerative disorders tied to mutations in the LMNA gene. This discovery sheds light on MLIP’s evolution, as it is uniquely found in amniotes [27], suggesting its emergence as an evolutionary novelty in these organisms. MLIP is characterized by alternatively spliced variants [27,29], showing a broad expression spectrum with a predominance in muscular tissues. Its interaction with lamin A/C and co-localization with promyelocytic leukemia (PML) bodies [27] suggest a vital role in cellular organization and differentiation, hinting at its contribution to the mesenchymal phenotypes observed in laminopathies.
Parallel to the original discovery of MLIP, the identification of cardiac Isl1-interacting protein (CIP, an alias of MLIP) [33] provided insights into cardiac hypertrophy’s regulatory mechanisms [34], underscoring its repressive role in cardiomyocyte hypertrophy and downregulation in hypertrophic conditions. CIP’s interaction with Isl1, essential for cardiac progenitor specification [34], emphasizes its regulatory capacity in cardiac development and hypertrophy. Further studies elucidated MLIP’s essential roles in cardiac and skeletal muscle function. For instance, MLIP deletion or overexpression significantly impacted the Akt/mTOR pathways [28], highlighting its potential as a cardiac stress sensor. This insight and genome-wide association studies linking MLIP to the cardiac stress response [28] underscores its therapeutic potential in cardiac diseases.
The exploration into MLIP’s function revealed its interaction with chromatin [26], suggesting a role in regulating muscle-specific gene networks and highlighting its importance in muscle differentiation and maintenance. This chromatin association and its ability to influence myoblast differentiation [26] positions MLIP as a critical factor in muscle physiology [30]. Moreover, studies revealed MLIP’s potential link to cancer through its involvement in gene networks related to cellular stress responses, including those mediated by p53 [28] and FOXO [31]. Such connections suggest a broader role for MLIP in cellular homeostasis and disease, including potential implications in cancer biology.

3. MLIP Expression in Cancer

Limited research has focused on elucidating the role of MLIP in the initiation and/or progression of cancer. Our investigation identified two primary types of cancers where MLIP’s role was emphasized: breast cancer and esophageal cancer (Table 1).
Breast cancer and esophageal cancer represent significant global health challenges, with the former being one of the most prevalent cancers among women and the latter noted for its particularly low survival rates [38,39]. The genetic underpinnings of these cancers are complex, and though substantial progress has been made in identifying key genetic risk factors, a significant proportion of the genetic risk remains unexplained. Recent research has begun to shed light on this gap, with a particular focus on the role of copy number variants (CNVs) and differentially expressed genes. One gene that has emerged as a potential key player in both breast and esophageal cancer is the MLIP gene.

Expression of MLIP in Different Types of Cancer

Breast cancer stands as one of the prevalent malignancies affecting women, with around one million new cases and over 400,000 reported deaths annually worldwide. In the year 2023, an estimated 297,790 women and 2800 men were projected to be diagnosed with breast cancer [40]. While single nucleotide polymorphisms and mutations contribute to approximately 49% of the genetic risk associated with breast cancer [41,42], Kumaran and colleagues (2017) sought to uncover the remaining 51% by identifying germline copy number variants (CNVs) linked to breast cancer [39]. Whole genome CNV genotyping was performed on 422 cases and 348 controls. Two hundred CNVs were identified to be associated with breast cancer of which 21 CNV regions overlapped with 22 genes. MLIP was identified as one of six genes associated with the breast cancer risk and recurrence-free survival [39]. Specifically, Kumaran and colleagues reported that a loss in MLIP CNVs was associated with significant reduction in the breast cancer risk and recurrence-free survival, with a reported hazard ratio of 0.62 [0.4–0.94] [39].
Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that is defined by the absence of estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 expression. These receptors are commonly used as targets for breast cancer treatment, and the absence of these receptors in TNBC makes it more difficult to treat. Zhang and colleagues performed RNA-seq on 30 TNBC patient tumors, 15 of which had lymph node metastasis while the other 15 showed no lymph node metastasis [32]. Differential gene expression analysis was performed in order to determine the key genes involved in the progression and oncogenesis of TNBC [32]. The analysis revealed 2953 genes with differential expression in breast tumors compared to normal control tissues and 975 genes with differential expression between 15 patients with lymph node metastasis and 15 patients without. A subset of 117 genes exhibited differential expression in both sets among those with and without lymph node metastasis in triple-negative breast cancer (TNBC), implying their involvement in TNBC oncogenesis and progression. Among the 117 genes of interest, MLIP was found to be upregulated in TNBC and exhibited a negative association with the cytotoxicity of CD8+ T cells [32].
Esophageal cancer is one of the most common malignancies, ranking seventh in global morbidity and sixth in cancer-related mortality. The 5-year overall survival rate is only about 15–20%, although progress has been made in diagnosis and treatment [38]. To further define prognostic mRNAs of esophageal cancer, functional enrichment analyses of lncRNA, mRNA, and miRNA in 81 tumors and 11 normal control tissues was performed. MLIP was identified as one of seven risk RNAs for esophageal cancer with a hazard ratio of 1.67 (1.22–2.29, p < 0.001) [38].
Finally, according to the recently found role of MLIP in cancer (Table 1), it has been suggested as a potential biomarker for triple-negative breast cancer and esophageal cancer. However, more research is needed to fully understand MLIP’s role in these cancers and its potential as a therapeutic target or diagnostic tool.

4. Molecular Relationship of MLIP with Pro-Survival/Oncogenic Pathways and Tumor Suppressors

The intricate network of cellular signaling pathways that govern cell growth, proliferation, survival, and metabolism is often dysregulated in various cancer types, contributing to tumorigenesis and disease progression. Central to this network are the PI3K/Akt/mTOR, FOXO, AMPK, p53, and lamin A/C pathways, each playing critical roles in maintaining cellular homeostasis and responding to stress signals. Recently, MLIP has emerged as a key interactor/regulator of the PI3K/Akt/mTOR, FOXO, AMPK, p53, and lamin A/C pathways (Figure 1), influencing a variety of cellular processes and potentially playing roles in both cancer pathogenesis and cardiac disorders.

4.1. MLIP: AMPK Function and Dysfunction in Cancer

The study by Cattin et al. in 2015 sheds light on the molecular mechanisms underlying the reduced glucose uptake observed in MLIP-deficient cardiac tissues [28]. In MLIP-deficient hearts, adenosine monophosphate-activated protein kinase (AMPK) was reported to undergo dephosphorylation at AMPK alpha-Thr-172, a crucial step leading to the deactivation of the AMPK complex and subsequently resulting in decreased glucose uptake compared to normal cardiac tissues [28]. Remarkably, this deactivation of AMPK occurred despite similar activity of liver kinase B1 (LKB1), the kinase responsible for AMPK activation [43], indicating an LKB1-independent inactivation of AMPK in MLIP-deficient hearts.
AMPK serves as a pivotal enzyme governing the cellular energy balance. Its primary function involves detecting shifts in the cellular energy status, particularly reductions in ATP, and initiating processes that generate ATP while concurrently inhibiting ATP-consuming processes. AMPK functions as a heterotrimeric complex, comprising catalytic α subunits and regulatory β and γ subunits. The γ subunit accommodates binding sites for AMP and ATP, enabling AMPK to sense alterations in the AMP/ATP ratio and self-activate during energy depletion. AMPK activation triggers diverse downstream effects, including heightened glucose uptake, fatty acid oxidation, and mitochondrial biogenesis, along with diminished protein synthesis, lipogenesis, and gluconeogenesis. AMPK also influences autophagy, cell growth, proliferation, and inflammation [44,45]. In response to stressors causing ATP depletion, such as hypoxia and glucose deprivation, AMPK activity is heightened [44,45]. Additionally, stimulating AMPK in skeletal muscle enhances glucose uptake and fatty acid oxidation while reducing lipid accumulation and inflammation [46]. These findings, combined with other research, collectively underscore the crucial role of AMPK in governing energy metabolism and cellular function.
The precise function of AMPK in cancer cells is complicated and relies on the specific context of AMPK activation. In certain instances, AMPK activation can serve as a tumor suppressor by restraining cell growth, curbing proliferation, and encouraging apoptosis. However, in other scenarios, AMPK activation might support the survival of tumor cells by facilitating metabolic adaptation to the unique conditions of the tumor microenvironment. Hence, targeting AMPK activation could be a problematic or promising approach for cancer treatment (Figure 2) [47]. Additionally, research indicates that combining AMPK activation with other anticancer therapies like chemotherapy or radiation has the potential to augment their effectiveness [47,48].
Interactions between MLIP and AMPK may hold implications for cancer biology. AMPK, recognized as a metabolic tumor suppressor, hampers cell growth and proliferation during low energy conditions, thereby impeding the uncontrolled cell growth characteristic of cancer [49]. Consequently, the observed reduction in AMPK activation in the absence of MLIP might potentially elevate the risk of unregulated cell growth and proliferation, contributing to oncogenesis. Furthermore, the decline in AMPK levels in MLIP-deficient cardiac tissues led to the heightened activation of the Akt/mTOR pathway [28,50]. This pathway significantly influences cell growth, proliferation, and survival, and its dysregulation is commonly observed in various types of cancers. These findings suggest that MLIP could potentially modulate these crucial pathways, thereby influencing cancer biology [28,49,50]. However, it is crucial to acknowledge that these observations were made specifically in cardiac tissue, and it remains uncertain whether similar mechanisms would apply to other tissues or cancer cells. Additional research is required to directly investigate the involvement of MLIP in cancer biology.

4.2. MLIP and the PI3K/Akt/mTOR Pathway

The documented association between MLIP and the PI3K/AKT/mTOR signaling pathway is evident in research findings that highlight MLIP’s direct impact on this pathway [28]. Specifically, the absence of MLIP leads to the selective hyperactivation of the Akt/mTOR signaling pathway in cardiac cells (Figure 3) [28]. Conversely, MLIP overexpression results in the inhibition of this pathway. The study demonstrates that the hyperactivation of Akt/mTOR occurs in cardiac cells when MLIP is absent [28]. These results suggest that a deficiency in MLIP may potentially contribute to an accelerated aging phenomenon within cardiac cells, heightening susceptibility to tumor development.
The regulatory link between MLIP and the PI3K/AKT/mTOR pathway is underscored by research indicating MLIP’s direct influence on this critical signaling pathway [28]. The absence of MLIP leads to the selective hyperactivation of the Akt/mTOR pathway in cardiac cells, as evidenced by the significant increase in pathway activity in MLIP-deficient cells. Conversely, MLIP overexpression results in the inhibition of this pathway, highlighting MLIP’s role as a negative regulator [28,31]. This hyperactivation of the Akt/mTOR pathway in the absence of MLIP suggests that MLIP deficiency may accelerate aging in cells and may heighten their susceptibility to tumor development, potentially implicating MLIP in cancer biology. The PI3K/Akt/mTOR pathway is crucial for regulating cellular processes such as growth, proliferation, survival, and metabolism, and its dysregulation is frequently observed in various cancers. Activation of this pathway in cancer cells can occur through multiple mechanisms, including genetic mutations, activation of upstream growth factor receptors, and loss of negative regulators. This activation promotes increased cell proliferation, survival, and resistance to cell death, contributing to tumor growth and progression (Figure 4) [51,52,53,54]. Thus, MLIP deficiency could facilitate these oncogenic processes, suggesting that MLIP might be a novel target for cancer therapy. Targeting the PI3K/Akt/mTOR pathway (Table 2) has become a promising cancer treatment strategy [53,54], with several drugs in development and testing showing potential in preclinical and clinical studies. However, these therapies must balance effectiveness with minimizing toxicity, necessitating ongoing research to improve their selectivity and efficacy [51,53,54]. Understanding MLIP’s regulatory role may offer new insights into cancer treatment strategies, potentially leading to more effective interventions.

4.3. Role of MLIP in FOXO1 Signaling

FOXO genes are a subgroup of the forkhead family of transcription factors that play a critical role in regulating various cellular processes, including cell cycle control, DNA repair, apoptosis, and the oxidative stress response [86,87,88,89]. Notably, the deletion of MLIP has also been linked to the downregulation of the FOXO1 pathway [28,31]. This suggests that the transcription factor FOXO-1 operates as a downstream signal of MLIP.
Dysregulation of FOXO gene expression or activity has been reported to be associated with the development and progression of cancer [90]. There are four members of the FOXO family in mammals: FOXO1, FOXO3, FOXO4, and FOXO6. Among these, FOXO1 and FOXO3 are the most well-studied in the context of cancer (Table 3). In normal cells, FOXO1 and FOXO3 are often activated in response to cellular stress, leading to the expression of target genes that promote cell cycle arrest, DNA repair, and apoptosis. This helps to prevent the development of cancer by eliminating cells with damaged DNA [91]. However, in cancer cells, the activity of FOXO1 and FOXO3 is often dysregulated [92,93,94]. In tumors, FOXO expression or activity is often suppressed to promote cell proliferation and survival, or alternatively, FOXO may be activated to promote cell migration and invasion [92,93,94].
FOXO1 has been found to play a role in the regulation of estrogen receptor (ER) signaling. In breast cancer, the loss of FOXO1 activity is associated with resistance to endocrine therapy, while overexpression of FOXO1 has been shown to sensitize breast cancer cells to endocrine therapy [35]. Likewise, in prostate cancer, FOXO3 has been identified as a partiCIPant in the control of androgen receptor signaling [94]. Reduced FOXO3 activity has been linked to resistance to androgen deprivation therapy, whereas increased FOXO3 expression has demonstrated the ability to enhance the sensitivity of prostate cancer cells to this therapy.
Although the precise mechanism through which MLIP increases FOXO-1 expression remains unknown, FOXO-1 is acknowledged for its involvement in cell cycle arrest, apoptosis, and tumor suppression, implying a potential role for MLIP in cancer pathogenesis. The activation of FOXO1 prompts the transcription of the cyclin-dependent kinase inhibitor p27KIP1 while suppressing the transcription of cyclin D1 and D2. Both effects result in cell cycle arrest at G1 phase. The loss of one allele of FOXO may render cells susceptible to dysregulated cell cycle events, triggering tumor formation. Activation of MLIP may mitigate the impact of FOXO haploinsufficiency on tumorigenesis.

4.4. MLIP and P53

MLIP-deficient hearts were found to have increased activation of p53 [28], indicating that MLIP-deficient hearts may be experiencing genotoxic and/or metabolic stress. The p53 gene functions as a crucial tumor suppressor, actively preventing cancer development by regulating various cellular processes, including DNA repair, cell cycle arrest, apoptosis, and senescence [7,8,37,95,96,97]. In response to DNA damage, p53 is activated, enabling it to pause the cell cycle for DNA repair or initiate apoptosis to eliminate damaged cells. In cancer, the p53 gene is frequently mutated or deleted, resulting in the loss of its tumor suppressor function [12,98]. Mutations in p53 represent one of the most prevalent genetic alterations in cancer, with up to 50% of all human cancers exhibiting p53 mutations [99,100]. The functional loss of p53 contributes to cancer development and progression by allowing the proliferation of damaged cells, facilitating the accumulation of additional genetic changes that can lead to cancer formation.
Beyond its role in the DNA damage response, p53 also partiCIPates in the regulation of cellular metabolism [101,102,103]. P53 has been demonstrated to influence the expression of genes involved in glycolysis, oxidative phosphorylation [104,105], and fatty acid metabolism [101,106]. P53 loss or mutation can contribute to the metabolic rewiring commonly observed in cancer cells [107]. However, the activation of p53 is triggered by other genes and is crucial for its role as a tumor suppressor [8]. This implies a potential alternative function of MLIP, wherein it may promote tumor formation by inhibiting p53, a critical tumor suppressor gene. Alternatively, MLIP inhibition might impact p53 function by influencing other genes associated with p53 activation.
Based on the findings of increased activation of p53 in MLIP-deficient hearts, one can speculate that MLIP may play a role in modulating p53 function in cancer. This potential role could involve MLIP influencing p53 activation and its associated pathways, either through direct interaction or by impacting other genes involved in p53 regulation. Understanding this relationship may provide novel insights into how MLIP contributes to cancer development and progression, particularly through its interaction with the crucial tumor suppressor gene p53.

4.5. MLIP and MAPK9 (Jak2)

The global mapping of the human binary protein interactome revealed and confirmed the interaction between MLIP and MAPK9 [108]. MAPK9, also known as JNK2, interacts intricately with several key signaling pathways, significantly impacting cellular processes and cancer biology [109,110]. One of its crucial interactions is with the PI3K/Akt/mTOR pathway, a major regulator of cell growth, proliferation, and survival [3,111,112]. MAPK9 modulates this pathway through phosphorylation events, often inhibiting PI3K/Akt activity under stress conditions and thus promoting apoptosis over cell survival [111]. This interaction can form a negative feedback loop that counterbalances the pro-survival signals from PI3K/Akt/mTOR, maintaining cellular equilibrium.
In relation to the tumor suppressor p53, MAPK9 plays a pivotal role in enhancing p53 activity through phosphorylation [113,114]. This phosphorylation stabilizes p53, particularly in response to cellular stress and DNA damage, leading to the activation of p53-dependent apoptotic genes [113,115]. Through this mechanism, MAPK9 contributes to the elimination of cells with damaged DNA, acting as a barrier against malignant transformation.
MAPK9 also interacts with FOXO transcription factors, which are key regulators of apoptosis, cell cycle arrest, and oxidative stress resistance. MAPK9 phosphorylates FOXO proteins, promoting their nuclear translocation and subsequent activation of stress response genes [111]. This regulation by MAPK9 is crucial for cellular responses to oxidative damage, helping to maintain cellular integrity and prevent uncontrolled proliferation. Overall, MAPK9′s interactions with MLIP, the PI3K/Akt/mTOR pathway, p53, and FOXO transcription factors create a complex network (Figure 1) that governs cell survival, apoptosis, and stress responses. These molecular relationships underscore how MLIP may have a multifaceted role in maintaining cellular homeostasis and its possible role in cancer progression.

5. Conclusions and MLIP as a Potential Therapeutic Target

MLIP is an emerging factor implicated in the regulation of key signaling pathways that govern cell growth, proliferation, survival, and metabolism, which are often dysregulated in cancer. Through its interactions with the PI3K/Akt/mTOR pathway, MLIP appears to exert an inhibitory effect [28]. Overexpression of MLIP leads to the downregulation of this pathway, while its loss results in the pathway’s overactivation [28,31,34,116]. This implies that MLIP might act as a suppressor of cell growth and proliferation, two key processes that are often hyperactivated in cancer. Therefore, therapies aimed at enhancing MLIP expression or its regulatory effect on the PI3K/Akt/mTOR pathway might be beneficial for inhibiting cancer progression.
Moreover, MLIP appears to be involved in the regulation of FOXO1 signaling [31], a pathway that plays critical roles in cell cycle control, apoptosis, and DNA repair—processes that are crucial for maintaining genomic integrity and preventing tumorigenesis. Dysregulation of FOXO1 signaling is often associated with cancer progression. Given that the deletion of MLIP leads to a downregulation of the FOXO1 pathway, and overexpression of MLIP is likely to have the opposite effect, therapeutics aimed at enhancing MLIP function or expression could potentially restore the normal function of FOXO1 signaling, thereby inhibiting cancer development and progression.
Additionally, MLIP’s interactions with p53 [28], a well-known tumor suppressor gene, further underscore its potential as a therapeutic target. Given that MLIP-deficient cardiomyocytes showed an increased expression of p53, it is plausible to hypothesize that MLIP could play a role in the regulation of p53, and by extension, cell cycle control and apoptosis.
However, it is essential to remember that the exact mechanisms of MLIP in these signaling pathways are not fully understood, and further research is necessary to establish MLIP as a therapeutic target. Furthermore, it is crucial to understand the potential off-target effects and safety profile of any MLIP-targeting therapies due to MLIP’s role in non-cancerous cells and processes, especially within the context of cardiac tissue where MLIP deficiency increase the susceptibility to developing heart failure [28,31] In summary, the modulation of MLIP’s function or its interactions with key signaling pathways represents a promising approach for the development of novel cancer therapeutics.

Author Contributions

All authors contributed to writing and editing this review. All authors have read and agreed to the published version of the manuscript.

Funding

All authors were supported by an Undergraduate Research Experience Program (UREP29-039-1-011) Award from QRDI.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Hanahan, D.; Weinberg, R.A. Hallmarks of Cancer: The next Generation. Cell 2011, 144, 646–674. [Google Scholar] [CrossRef] [PubMed]
  2. Matthews, H.K.; Bertoli, C.; de Bruin, R.A.M. Cell Cycle Control in Cancer. Nat. Rev. Mol. Cell Biol. 2022, 23, 74–88. [Google Scholar] [CrossRef] [PubMed]
  3. Paquette, M.; El-Houjeiri, L.; Pause, A. MTOR Pathways in Cancer and Autophagy. Cancers 2018, 10, 18. [Google Scholar] [CrossRef] [PubMed]
  4. Yu, L.; Wei, J.; Liu, P. Attacking the PI3K/Akt/MTOR Signaling Pathway for Targeted Therapeutic Treatment in Human Cancer. Semin. Cancer Biol. 2022, 85, 69–94. [Google Scholar] [CrossRef] [PubMed]
  5. Eijkelenboom, A.; Burgering, B.M.T. FOXOs: Signalling Integrators for Homeostasis Maintenance. Nat. Rev. Mol. Cell Biol. 2013, 14, 83–97. [Google Scholar] [CrossRef] [PubMed]
  6. Ronnebaum, S.M.; Patterson, C. The FOXO Family in Cardiac Function and Dysfunction. Annu. Rev. Physiol. 2010, 72, 81–94. [Google Scholar] [CrossRef] [PubMed]
  7. Vousden, K.H.; Ryan, K.M. P53 and Metabolism. Nat. Rev. Cancer 2009, 9, 691–700. [Google Scholar] [CrossRef]
  8. Vousden, K.H.; Prives, C. Blinded by the Light: The Growing Complexity of P53. Cell 2009, 137, 413–431. [Google Scholar] [CrossRef] [PubMed]
  9. Jose, E.; March-Steinman, W.; Wilson, B.A.; Shanks, L.; Paek, A.L. Temporal Coordination of the Transcription Factor Response to H2O2 Stress. Nat. Commun. 2024, 15, 3440. [Google Scholar] [CrossRef]
  10. Jȩśko, H.; Strosznajder, R.P. Sirtuins and Their Interactions with Transcription Factors and Poly(ADP-Ribose) Polymerases. Folia Neuropathol. 2016, 54, 212–233. [Google Scholar] [CrossRef]
  11. Vurusaner, B.; Poli, G.; Basaga, H. Tumor Suppressor Genes and ROS: Complex Networks of Interactions. Free Radic. Biol. Med. 2012, 52, 7–18. [Google Scholar] [CrossRef] [PubMed]
  12. Wang, Y.H.; Ho, T.L.F.; Hariharan, A.; Goh, H.C.; Wong, Y.L.; Verkaik, N.S.; Lee, M.Y.; Tam, W.L.; van Gent, D.C.; Venkitaraman, A.R.; et al. Rapid Recruitment of P53 to DNA Damage Sites Directs DNA Repair Choice and Integrity. Proc. Natl. Acad. Sci. USA 2022, 119, e2113233119. [Google Scholar] [CrossRef] [PubMed]
  13. Haapaniemi, E.; Botla, S.; Persson, J.; Schmierer, B.; Taipale, J. CRISPR-Cas9 Genome Editing Induces a P53-Mediated DNA Damage Response. Nat. Med. 2018, 24, 927–930. [Google Scholar] [CrossRef]
  14. Battiprolu, P.K.; Lopez-Crisosto, C.; Wang, Z.V.; Nemchenko, A.; Lavandero, S.; Hill, J.A. Diabetic Cardiomyopathy and Metabolic Remodeling of the Heart. Life Sci. 2013, 92, 609–615. [Google Scholar] [CrossRef] [PubMed]
  15. AbuEid, M.; McAllister, D.M.; McOlash, L.; Harwig, M.C.; Cheng, G.; Drouillard, D.; Boyle, K.A.; Hardy, M.; Zielonka, J.; Johnson, B.D.; et al. Synchronous Effects of Targeted Mitochondrial Complex I Inhibitors on Tumor and Immune Cells Abrogate Melanoma Progression. iScience 2021, 24, 102653. [Google Scholar] [CrossRef] [PubMed]
  16. Zečić, A.; Braeckman, B.P. DAF-16/FOXO in Caenorhabditis Elegans and Its Role in Metabolic Remodeling. Cells 2020, 9, 109. [Google Scholar] [CrossRef] [PubMed]
  17. Pavlova, N.N.; Thompson, C.B. The Emerging Hallmarks of Cancer Metabolism. Cell Metab. 2016, 23, 27–47. [Google Scholar] [CrossRef] [PubMed]
  18. De Berardinis, R.J.; Chandel, N.S. Fundamentals of Cancer Metabolism. Sci. Adv. 2016, 2, e1600200. [Google Scholar] [CrossRef] [PubMed]
  19. Faubert, B.; Solmonson, A.; DeBerardinis, R.J. Metabolic Reprogramming and Cancer Progression. Science 2020, 368, eaaw5473. [Google Scholar] [CrossRef]
  20. Jiang, Z.; He, J.; Zhang, B.; Wang, L.; Long, C.; Zhao, B.; Yang, Y.; Du, L.; Luo, W.; Hu, J.; et al. A Potential “Anti-Warburg Effect” in Circulating Tumor Cell-Mediated Metastatic Progression? Aging Dis. 2024. online ahead of print. [Google Scholar] [CrossRef]
  21. Liberti, M.V.; Locasale, J.W. The Warburg Effect: How Does It Benefit Cancer Cells? Trends Biochem. Sci. 2016, 41, 211–218. [Google Scholar] [CrossRef]
  22. Chae, H.S.; Hong, S.T. Overview of Cancer Metabolism and Signaling Transduction. Int. J. Mol. Sci. 2023, 24, 12. [Google Scholar] [CrossRef]
  23. Farhan, M.; Silva, M.; Xingan, X.; Huang, Y.; Zheng, W. Role of FOXO Transcription Factors in Cancer Metabolism and Angiogenesis. Cells 2020, 9, 1586. [Google Scholar] [CrossRef] [PubMed]
  24. Liu, J.; Peng, Y.; Wei, W. Cell Cycle on the Crossroad of Tumorigenesis and Cancer Therapy. Trends Cell Biol. 2022, 32, 30–44. [Google Scholar] [CrossRef] [PubMed]
  25. Wang, S.F.; Tseng, L.M.; Lee, H.C. Role of Mitochondrial Alterations in Human Cancer Progression and Cancer Immunity. J. Biomed. Sci. 2023, 30, 61. [Google Scholar] [CrossRef] [PubMed]
  26. Ahmady, E.; Blais, A.; Burgon, P.G. Muscle Enriched Lamin Interacting Protein (MLIP) Binds Chromatin and Is Required for Myoblast Differentiation. Cells 2021, 10, 615. [Google Scholar] [CrossRef] [PubMed]
  27. Ahmady, E.; Deeke, S.A.; Rabaa, S.; Kouri, L.; Kenney, L.; Stewart, A.F.R.; Burgon, P.G. Identification of a Novel Muscle A-Type Lamin-Interacting Protein (MLIP). J. Biol. Chem. 2011, 286, 19702–19713. [Google Scholar] [CrossRef] [PubMed]
  28. Cattin, M.-E.; Wang, J.; Weldrick, J.J.; Roeske, C.L.; Mak, E.; Thorn, S.L.; DaSilva, J.N.; Wang, Y.; Lusis, A.J.; Burgon, P.G. Deletion of MLIP (Muscle-Enriched A-Type Lamin-Interacting Protein) Leads to Cardiac Hyperactivation of Akt/Mammalian Target of Rapamycin (MTOR) and Impaired Cardiac Adaptation. J. Biol. Chem. 2015, 290, 26699–26714. [Google Scholar] [CrossRef] [PubMed]
  29. Cattin, M.-E.; Deeke, S.A.; Dick, S.A.; Verret-Borsos, Z.J.A.; Tennakoon, G.; Gupta, R.; Mak, E.; Roeske, C.L.; Weldrick, J.J.; Megeney, L.A.; et al. Expression of Murine Muscle-Enriched A-Type Lamin-Interacting Protein (MLIP) Is Regulated by Tissue-Specific Alternative Transcription Start Sites. J. Biol. Chem. 2018, 293, 19761–19770. [Google Scholar] [CrossRef] [PubMed]
  30. Lopes Abath Neto, O.; Medne, L.; Donkervoort, S.; Rodríguez-García, M.E.; Bolduc, V.; Hu, Y.; Guadagnin, E.; Foley, A.R.; Brandsema, J.F.; Glanzman, A.M.; et al. MLIP Causes Recessive Myopathy with Rhabdomyolysis, Myalgia and Baseline Elevated Serum Creatine Kinase. Brain 2021, 144, 2722–2731. [Google Scholar] [CrossRef]
  31. Huang, Z.-P.; Kataoka, M.; Chen, J.; Wu, G.; Ding, J.; Nie, M.; Lin, Z.; Liu, J.; Hu, X.; Ma, L.; et al. Cardiomyocyte-Enriched Protein CIP Protects against Pathophysiological Stresses and Regulates Cardiac Homeostasis. J. Clin. Investig. 2015, 125, 4122–4134. [Google Scholar] [CrossRef]
  32. Zhang, Y.; Tong, G.H.; Wei, X.X.; Chen, H.Y.; Liang, T.; Tang, H.P.; Wu, C.A.; Wen, G.M.; Yang, W.K.; Liang, L.; et al. Identification of Five Cytotoxicity-Related Genes Involved in the Progression of Triple-Negative Breast Cancer. Front. Genet. 2022, 12, 723477. [Google Scholar] [CrossRef]
  33. Burgon, P. Human Genome Organization—Symbolized Muscle-Enriched a-Type Lamin-Interacting Protein to Clear up Confusion. Circ. Res. 2012, 111, e252; author reply e253-4. [Google Scholar] [CrossRef] [PubMed]
  34. Huang, Z.-P.; Young Seok, H.; Zhou, B.; Chen, J.J.-F.; Chen, J.J.-F.; Tao, Y.; Pu, W.T.; Wang, D.-Z. CIP, a Cardiac Isl1-Interacting Protein, Represses Cardiomyocyte Hypertrophy. Circ. Res. 2012, 110, 818–830. [Google Scholar] [CrossRef]
  35. Bullock, M. FOXO Factors and Breast Cancer: Outfoxing Endocrine Resistance. Endocr. Relat. Cancer 2016, 23, R113–R130. [Google Scholar] [CrossRef] [PubMed]
  36. Yu, W.; Chen, C.; Cheng, J. The Role and Molecular Mechanism of FOXO1 in Mediating Cardiac Hypertrophy. ESC Heart Fail. 2020, 7, 3497–3504. [Google Scholar] [CrossRef] [PubMed]
  37. Helton, E.S.; Chen, X. P53 Modulation of the DNA Damage Response. J. Cell Biochem. 2007, 100, 883–896. [Google Scholar] [CrossRef]
  38. Shi, X.; Li, Y.; Sun, Y.; Zhao, X.; Sun, X.; Gong, T.; Liang, Z.; Ma, Y.; Zhang, X. Genome-Wide Analysis of LncRNAs, MiRNAs, and MRNAs Forming a Prognostic Scoring System in Esophageal Squamous Cell Carcinoma. PeerJ 2020, 2020, e8368. [Google Scholar] [CrossRef]
  39. Kumaran, M.; Cass, C.E.; Graham, K.; Mackey, J.R.; Hubaux, R.; Lam, W.; Yasui, Y.; Damaraju, S. Germline Copy Number Variations Are Associated with Breast Cancer Risk and Prognosis. Sci. Rep. 2017, 7, 14621. [Google Scholar] [CrossRef]
  40. Breast Cancer Facts & Stats|Incidence, Age, Survival, & More. Available online: https://www.nationalbreastcancer.org/breast-cancer-facts/ (accessed on 26 October 2023).
  41. Michailidou, K.; Hall, P.; Gonzalez-Neira, A.; Ghoussaini, M.; Dennis, J.; Milne, R.L.; Schmidt, M.K.; Chang-Claude, J.; Bojesen, S.E.; Bolla, M.K.; et al. Large-Scale Genotyping Identifies 41 New Loci Associated with Breast Cancer Risk. Nat. Genet. 2013, 45, 353–361. [Google Scholar] [CrossRef]
  42. Fachal, L.; Dunning, A.M. From Candidate Gene Studies to GWAS and Post-GWAS Analyses in Breast Cancer. Curr. Opin. Genet. Dev. 2015, 30, 32–41. [Google Scholar] [CrossRef]
  43. Lin, S.C.; Hardie, D.G. AMPK: Sensing Glucose as Well as Cellular Energy Status. Cell Metab. 2018, 27, 299–313. [Google Scholar] [CrossRef] [PubMed]
  44. Salt, I.P.; Johnson, G.; Ashcroft, S.J.H.; Hardie, D.G. AMP-Activated Protein Kinase Is Activated by Low Glucose in Cell Lines Derived from Pancreatic Beta Cells, and May Regulate Insulin Release. Biochem. J. 1998, 335 Pt 3, 533–539. [Google Scholar] [CrossRef]
  45. Yan, Y.; Zhou, X.E.; Xu, H.E.; Melcher, K. Structure and Physiological Regulation of AMPK. Int. J. Mol. Sci. 2018, 19, 3534. [Google Scholar] [CrossRef]
  46. Liong, S.; Lappas, M. Activation of AMPK Improves Inflammation and Insulin Resistance in Adipose Tissue and Skeletal Muscle from Pregnant Women. J. Physiol. Biochem. 2015, 71, 703–717. [Google Scholar] [CrossRef] [PubMed]
  47. Li, W.; Saud, S.M.; Young, M.R.; Chen, G.; Hua, B. Targeting AMPK for Cancer Prevention and Treatment. Oncotarget 2015, 6, 7365–7378. [Google Scholar] [CrossRef] [PubMed]
  48. Keerthana, C.K.; Rayginia, T.P.; Shifana, S.C.; Anto, N.P.; Kalimuthu, K.; Isakov, N.; Anto, R.J. The Role of AMPK in Cancer Metabolism and Its Impact on the Immunomodulation of the Tumor Microenvironment. Front. Immunol. 2023, 14, 1114582. [Google Scholar] [CrossRef]
  49. Luo, Z.; Zang, M.; Guo, W. AMPK as a Metabolic Tumor Suppressor: Control of Metabolism and Cell Growth. Future Oncol. 2010, 6, 457–470. [Google Scholar] [CrossRef] [PubMed]
  50. Sung, M.M.; Zordoky, B.N.; Bujak, A.L.; Lally, J.S.V.; Fung, D.; Young, M.E.; Horman, S.; Miller, E.J.; Light, P.E.; Kemp, B.E.; et al. AMPK Deficiency in Cardiac Muscle Results in Dilated Cardiomyopathy in the Absence of Changes in Energy Metabolism. Cardiovasc. Res. 2015, 107, 235–245. [Google Scholar] [CrossRef] [PubMed]
  51. Alzahrani, A.S. PI3K/Akt/MTOR Inhibitors in Cancer: At the Bench and Bedside. Semin. Cancer Biol. 2019, 59, 125–132. [Google Scholar] [CrossRef]
  52. Ediriweera, M.K.; Tennekoon, K.H.; Samarakoon, S.R. Role of the PI3K/AKT/MTOR Signaling Pathway in Ovarian Cancer: Biological and Therapeutic Significance. Semin. Cancer Biol. 2019, 59, 147–160. [Google Scholar] [CrossRef]
  53. Polivka, J.; Janku, F. Molecular Targets for Cancer Therapy in the PI3K/AKT/MTOR Pathway. Pharmacol. Ther. 2014, 142, 164–175. [Google Scholar] [CrossRef] [PubMed]
  54. Mayer, I.A.; Arteaga, C.L. The PI3K/AKT Pathway as a Target for Cancer Treatment. Annu. Rev. Med. 2016, 67, 11–28. [Google Scholar] [CrossRef] [PubMed]
  55. Bou Zeid, N.; Yazbeck, V. PI3k Inhibitors in NHL and CLL: An Unfulfilled Promise. Blood Lymphat. Cancer 2023, 13, 1–12. [Google Scholar] [CrossRef] [PubMed]
  56. Krause, G.; Hassenrück, F.; Hallek, M. Copanlisib for Treatment of B-Cell Malignancies: The Development of a PI3K Inhibitor with Considerable Differences to Idelalisib. Drug Des. Devel Ther. 2018, 12, 2577–2590. [Google Scholar] [CrossRef] [PubMed]
  57. Patel, K.; Danilov, A.V.; Pagel, J.M. Duvelisib for CLL/SLL and Follicular Non-Hodgkin Lymphoma. Blood 2019, 134, 1573–1577. [Google Scholar] [CrossRef] [PubMed]
  58. Langer, C.J.; Redman, M.W.; Wade, J.L.; Aggarwal, C.; Bradley, J.D.; Crawford, J.; Stella, P.J.; Knapp, M.H.; Miao, J.; Minichiello, K.; et al. SWOG S1400B (NCT02785913), a Phase II Study of GDC-0032 (Taselisib) for Previously Treated PI3K-Positive Patients with Stage IV Squamous Cell Lung Cancer (Lung-MAP Sub-Study). J. Thorac. Oncol. 2019, 14, 1839–1846. [Google Scholar] [CrossRef] [PubMed]
  59. Turner, S.; Chia, S.; Kanakamedala, H.; Hsu, W.C.; Park, J.; Chandiwana, D.; Ridolfi, A.; Yu, C.L.; Zarate, J.P.; Rugo, H.S. Effectiveness of Alpelisib + Fulvestrant Compared with Real-World Standard Treatment Among Patients with HR+, HER2-, PIK3CA-Mutated Breast Cancer. Oncologist 2021, 26, e1133–e1142. [Google Scholar] [CrossRef] [PubMed]
  60. Bertho, M.; Patsouris, A.; Augereau, P.; Robert, M.; Frenel, J.S.; Blonz, C.; Campone, M. A Pharmacokinetic Evaluation of Alpelisib for the Treatment of HR+, HER2-Negative, PIK3CA-Mutated Advanced or Metastatic Breast Cancer. Expert. Opin. Drug Metab. Toxicol. 2021, 17, 139–152. [Google Scholar] [CrossRef] [PubMed]
  61. Sarker, D.; Ang, J.E.; Baird, R.; Kristeleit, R.; Shah, K.; Moreno, V.; Clarke, P.A.; Raynaud, F.I.; Levy, G.; Ware, J.A.; et al. First-in-Human Phase I Study of Pictilisib (GDC-0941), a Potent Pan-Class I Phosphatidylinositol-3-Kinase (PI3K) Inhibitor, in Patients with Advanced Solid Tumors. Clin. Cancer Res. 2015, 21, 77–86. [Google Scholar] [CrossRef]
  62. Munster, P.; Aggarwal, R.; Hong, D.; Schellens, J.H.M.; Van Der Noll, R.; Specht, J.; Witteveen, P.O.; Werner, T.L.; Dees, E.C.; Bergsland, E.; et al. First-in-Human Phase I Study of GSK2126458, an Oral Pan-Class I Phosphatidylinositol-3-Kinase Inhibitor, in Patients with Advanced Solid Tumor Malignancies. Clin. Cancer Res. 2016, 22, 1932–1939. [Google Scholar] [CrossRef]
  63. De Bono, J.S.; De Giorgi, U.; Rodrigues, D.N.; Massard, C.; Bracarda, S.; Font, A.; Arija, J.A.A.; Shih, K.C.; Radavoi, G.D.; Xu, N.; et al. Randomized Phase II Study Evaluating Akt Blockade with Ipatasertib, in Combination with Abiraterone, in Patients with Metastatic Prostate Cancer with and without PTEN Loss. Clin. Cancer Res. 2019, 25, 928–936. [Google Scholar] [CrossRef]
  64. Bang, Y.J.; Kang, Y.K.; Ng, M.; Chung, H.C.; Wainberg, Z.A.; Gendreau, S.; Chan, W.Y.; Xu, N.; Maslyar, D.; Meng, R.; et al. A Phase II, Randomised Study of MFOLFOX6 with or without the Akt Inhibitor Ipatasertib in Patients with Locally Advanced or Metastatic Gastric or Gastroesophageal Junction Cancer. Eur. J. Cancer 2019, 108, 17–24. [Google Scholar] [CrossRef] [PubMed]
  65. Turner, N.C.; Oliveira, M.; Howell, S.J.; Dalenc, F.; Cortes, J.; Gomez Moreno, H.L.; Hu, X.; Jhaveri, K.; Krivorotko, P.; Loibl, S.; et al. Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer. N. Engl. J. Med. 2023, 388, 2058–2070. [Google Scholar] [CrossRef] [PubMed]
  66. Forde, K.; Resta, N.; Ranieri, C.; Rea, D.; Kubassova, O.; Hinton, M.; Andrews, K.A.; Semple, R.; Irvine, A.D.; Dvorakova, V. Clinical Experience with the AKT1 Inhibitor Miransertib in Two Children with PIK3CA-Related Overgrowth Syndrome. Orphanet J. Rare Dis. 2021, 16, 109. [Google Scholar] [CrossRef]
  67. Tolcher, A.W.; Patnaik, A.; Papadopoulos, K.P.; Rasco, D.W.; Becerra, C.R.; Allred, A.J.; Orford, K.; Aktan, G.; Ferron-Brady, G.; Ibrahim, N.; et al. Phase I Study of the MEK Inhibitor Trametinib in Combination with the AKT Inhibitor Afuresertib in Patients with Solid Tumors and Multiple Myeloma. Cancer Chemother. Pharmacol. 2015, 75, 183–189. [Google Scholar] [CrossRef] [PubMed]
  68. Aghajanian, C.; Bell-McGuinn, K.M.; Burris, H.A.; Siu, L.L.; Stayner, L.A.; Wheler, J.J.; Hong, D.S.; Kurkjian, C.; Pant, S.; Santiago-Walker, A.; et al. A Phase I, Open-Label, Two-Stage Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Oral AKT Inhibitor GSK2141795 in Patients with Solid Tumors. Invest. New Drugs 2018, 36, 1016–1025. [Google Scholar] [CrossRef] [PubMed]
  69. Myers, A.P.; Konstantinopoulos, P.A.; Barry, W.T.; Luo, W.; Broaddus, R.R.; Makker, V.; Drapkin, R.; Liu, J.; Doyle, A.; Horowitz, N.S.; et al. Phase II, 2-Stage, 2-Arm, PIK3CA Mutation Stratified Trial of MK-2206 in Recurrent Endometrial Cancer. Int. J. Cancer 2020, 147, 413–422. [Google Scholar] [CrossRef]
  70. Besse, B.; Leighl, N.; Bennouna, J.; Papadimitrakopoulou, V.A.; Blais, N.; Traynor, A.M.; Soria, J.C.; Gogov, S.; Miller, N.; Jehl, V.; et al. Phase II Study of Everolimus-Erlotinib in Previously Treated Patients with Advanced Non-Small-Cell Lung Cancer. Ann. Oncol. 2014, 25, 409–415. [Google Scholar] [CrossRef] [PubMed]
  71. Besse, B.; Heist, R.S.; Papadmitrakopoulou, V.A.; Camidge, D.R.; Beck, J.T.; Schmid, P.; Mulatero, C.; Miller, N.; Dimitrijevic, S.; Urva, S.; et al. A Phase Ib Dose-Escalation Study of Everolimus Combined with Cisplatin and Etoposide as First-Line Therapy in Patients with Extensive-Stage Small-Cell Lung Cancer. Ann. Oncol. 2014, 25, 505–511. [Google Scholar] [CrossRef]
  72. Gandhi, L.; Bahleda, R.; Tolaney, S.M.; Kwak, E.L.; Cleary, J.M.; Pandya, S.S.; Hollebecque, A.; Abbas, R.; Ananthakrishnan, R.; Berkenblit, A.; et al. Phase I Study of Neratinib in Combination with Temsirolimus in Patients with Human Epidermal Growth Factor Receptor 2-Dependent and Other Solid Tumors. J. Clin. Oncol. 2014, 32, 68–75. [Google Scholar] [CrossRef]
  73. Moran, T.; Palmero, R.; Provencio, M.; Insa, A.; Majem, M.; Reguart, N.; Bosch-Barrera, J.; Isla, D.; Costa, E.C.; Lee, C.; et al. A Phase Ib Trial of Continuous Once-Daily Oral Afatinib plus Sirolimus in Patients with Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer and/or Disease Progression Following Prior Erlotinib or Gefitinib. Lung Cancer 2017, 108, 154–160. [Google Scholar] [CrossRef] [PubMed]
  74. Pearson, A.D.J.; Federico, S.M.; Aerts, I.; Hargrave, D.R.; DuBois, S.G.; Iannone, R.; Geschwindt, R.D.; Wang, R.; Haluska, F.G.; Trippett, T.M.; et al. A Phase 1 Study of Oral Ridaforolimus in Pediatric Patients with Advanced Solid Tumors. Oncotarget 2016, 7, 84736–84747. [Google Scholar] [CrossRef] [PubMed]
  75. García-Saenz, J.A.; Martínez-Jañez, N.; Cubedo, R.; Jerez, Y.; Lahuerta, A.; Gonzalez-Santiago, S.; Ferrer, N.; Ramos, M.; Alonso-Romero, J.L.; Anton, A.; et al. Sapanisertib plus Fulvestrant in Postmenopausal Women with Estrogen Receptor-Positive/HER2-Negative Advanced Breast Cancer after Progression on Aromatase Inhibitor. Clin. Cancer Res. 2022, 28, 1107–1116. [Google Scholar] [CrossRef]
  76. Heudel, P.; Frenel, J.S.; Dalban, C.; Bazan, F.; Joly, F.; Arnaud, A.; Abdeddaim, C.; Chevalier-Place, A.; Augereau, P.; Pautier, P.; et al. Safety and Efficacy of the MTOR Inhibitor, Vistusertib, Combined with Anastrozole in Patients with Hormone Receptor-Positive Recurrent or Metastatic Endometrial Cancer: The VICTORIA Multicenter, Open-Label, Phase 1/2 Randomized Clinical Trial. JAMA Oncol. 2022, 8, 1001–1009. [Google Scholar] [CrossRef] [PubMed]
  77. Lang, F.; Wunderle, L.; Badura, S.; Schleyer, E.; Brüggemann, M.; Serve, H.; Schnittger, S.; Gökbuget, N.; Pfeifer, H.; Wagner, S.; et al. A Phase I Study of a Dual PI3-Kinase/MTOR Inhibitor BEZ235 in Adult Patients with Relapsed or Refractory Acute Leukemia. BMC Pharmacol. Toxicol. 2020, 21, 70. [Google Scholar] [CrossRef] [PubMed]
  78. Powles, T.; Lackner, M.R.; Oudard, S.; Escudier, B.; Ralph, C.; Brown, J.E.; Hawkins, R.E.; Castellano, D.; Rini, B.I.; Staehler, M.D.; et al. Randomized Open-Label Phase II Trial of Apitolisib (GDC-0980), a Novel Inhibitor of the PI3K/Mammalian Target of Rapamycin Pathway, versus Everolimus in Patients with Metastatic Renal Cell Carcinoma. J. Clin. Oncol. 2016, 34, 1660–1668. [Google Scholar] [CrossRef]
  79. Dolly, S.O.; Wagner, A.J.; Bendell, J.C.; Kindler, H.L.; Krug, L.M.; Seiwert, T.Y.; Zauderer, M.G.; Lolkema, M.P.; Apt, D.; Yeh, R.F.; et al. Phase I Study of Apitolisib (GDC-0980), Dual Phosphatidylinositol-3-Kinase and Mammalian Target of Rapamycin Kinase Inhibitor, in Patients with Advanced Solid Tumors. Clin. Cancer Res. 2016, 22, 2874–2884. [Google Scholar] [CrossRef] [PubMed]
  80. Tarantelli, C.; Gaudio, E.; Arribas, A.J.; Kwee, I.; Hillmann, P.; Rinaldi, A.; Cascione, L.; Spriano, F.; Bernasconi, E.; Guidetti, F.; et al. PQR309 Is a Novel Dual PI3K/MTOR Inhibitor with Preclinical Antitumor Activity in Lymphomas as a Single Agent and in Combination Therapy. Clin. Cancer Res. 2018, 24, 120–129. [Google Scholar] [CrossRef]
  81. Grilley-Olson, J.E.; Bedard, P.L.; Fasolo, A.; Cornfeld, M.; Cartee, L.; Razak, A.R.A.; Stayner, L.A.; Wu, Y.; Greenwood, R.; Singh, R.; et al. A Phase Ib Dose-Escalation Study of the MEK Inhibitor Trametinib in Combination with the PI3K/MTOR Inhibitor GSK2126458 in Patients with Advanced Solid Tumors. Investig. New Drugs 2016, 34, 740–749. [Google Scholar] [CrossRef]
  82. Wainberg, Z.A.; Alsina, M.; Soares, H.P.; Braña, I.; Britten, C.D.; Del Conte, G.; Ezeh, P.; Houk, B.; Kern, K.A.; Leong, S.; et al. A Multi-Arm Phase I Study of the PI3K/MTOR Inhibitors PF-04691502 and Gedatolisib (PF-05212384) plus Irinotecan or the MEK Inhibitor PD-0325901 in Advanced Cancer. Target. Oncol. 2017, 12, 775–785. [Google Scholar] [CrossRef]
  83. Morscher, R.J.; Brard, C.; Berlanga, P.; Marshall, L.V.; André, N.; Rubino, J.; Aerts, I.; De Carli, E.; Corradini, N.; Nebchi, S.; et al. First-in-Child Phase I/II Study of the Dual MTORC1/2 Inhibitor Vistusertib (AZD2014) as Monotherapy and in Combination with Topotecan-Temozolomide in Children with Advanced Malignancies: Arms E and F of the AcSé-ESMART Trial. Eur. J. Cancer 2021, 157, 268–277. [Google Scholar] [CrossRef] [PubMed]
  84. Choueiri, T.K.; Porta, C.; Suárez, C.; Hainsworth, J.; Voog, E.; Duran, I.; Reeves, J.; Czaykowski, P.; Castellano, D.; Chen, J.; et al. Randomized Phase II Trial of Sapanisertib ± TAK-117 vs. Everolimus in Patients with Advanced Renal Cell Carcinoma After VEGF-Targeted Therapy. Oncologist 2022, 27, 1048–1057. [Google Scholar] [CrossRef] [PubMed]
  85. Starks, D.C.; Rojas-Espaillat, L.; Meissner, T.; Williams, C.B. Phase I Dose Escalation Study of Dual PI3K/MTOR Inhibition by Sapanisertib and Serabelisib in Combination with Paclitaxel in Patients with Advanced Solid Tumors. Gynecol. Oncol. 2022, 166, 403–409. [Google Scholar] [CrossRef] [PubMed]
  86. Bernardo, V.S.; Torres, F.F.; da Silva, D.G.H. FOXO3 and Oxidative Stress: A Multifaceted Role in Cellular Adaptation. J. Mol. Med. 2023, 101, 83–99. [Google Scholar] [CrossRef] [PubMed]
  87. Tsitsipatis, D.; Klotz, L.O.; Steinbrenner, H. Multifaceted Functions of the Forkhead Box Transcription Factors FOXO1 and FOXO3 in Skin. Biochim. Biophys. Acta Gen. Subj. 2017, 1861, 1057–1064. [Google Scholar] [CrossRef]
  88. Hosaka, T.; Biggs, W.H.; Tieu, D.; Boyer, A.D.; Varki, N.M.; Cavenee, W.K.; Arden, K.C. Disruption of Forkhead Transcription Factor (FOXO) Family Members in Mice Reveals Their Functional Diversification. Proc. Natl. Acad. Sci. USA 2004, 101, 2975–2980. [Google Scholar] [CrossRef]
  89. Huang, H.; Tindall, D.J. Dynamic FOXO Transcription Factors. J. Cell Sci. 2007, 120, 2479–2487. [Google Scholar] [CrossRef] [PubMed]
  90. Jiramongkol, Y.; Lam, E.W.F. FOXO Transcription Factor Family in Cancer and Metastasis. Cancer Metastasis Rev. 2020, 39, 681–709. [Google Scholar] [CrossRef]
  91. Rodriguez-Colman, M.J.; Dansen, T.B.; Burgering, B.M.T. FOXO Transcription Factors as Mediators of Stress Adaptation. Nat. Rev. Mol. Cell Biol. 2023, 25, 46–64. [Google Scholar] [CrossRef]
  92. Freycon, C.; Lupo, P.J.; Witkowski, L.; Budd, C.; Foulkes, W.D.; Goudie, C. A Systematic Review of the Prevalence of Pathogenic or Likely Pathogenic Germline Variants in Individuals with FOXO1 Fusion-Positive Rhabdomyosarcoma. Pediatr. Blood Cancer 2023, 70, 30651. [Google Scholar] [CrossRef]
  93. Liu, Y.; Ao, X.; Ding, W.; Ponnusamy, M.; Wu, W.; Hao, X.; Yu, W.; Wang, Y.; Li, P.; Wang, J. Critical Role of FOXO3a in Carcinogenesis. Mol. Cancer 2018, 17, 104. [Google Scholar] [CrossRef]
  94. Habrowska-Górczyńska, D.E.; Kozieł, M.J.; Kowalska, K.; Piastowska-Ciesielska, A.W. FOXO3a and Its Regulators in Prostate Cancer. Int. J. Mol. Sci. 2021, 22, 12530. [Google Scholar] [CrossRef] [PubMed]
  95. Williams, A.B.; Schumacher, B. P53 in the DNA-Damage-Repair Process. Cold Spring Harb. Perspect. Med. 2016, 6, a026070. [Google Scholar] [CrossRef] [PubMed]
  96. Gnanasundram, S.V.; Bonczek, O.; Wang, L.; Chen, S.; Fahraeus, R. P53 MRNA Metabolism Links with the DNA Damage Response. Genes 2021, 12, 1446. [Google Scholar] [CrossRef] [PubMed]
  97. Albrechtsen, N.; Dornreiter, I.; Grosse, F.; Ella, K.; Wiesmüller, L.; Deppert, W. Maintenance of Genomic Integrity by P53: Complementary Roles for Activated and Non-Activated P53. Oncogene 1999, 18, 7706–7717. [Google Scholar] [CrossRef]
  98. Gatz, S.A.; Wiesmüller, L. P53 in Recombination and Repair. Cell Death Differ. 2006, 13, 1003–1016. [Google Scholar] [CrossRef] [PubMed]
  99. Duffy, M.J.; Synnott, N.C.; O’Grady, S.; Crown, J. Targeting P53 for the Treatment of Cancer. Semin. Cancer Biol. 2022, 79, 58–67. [Google Scholar] [CrossRef] [PubMed]
  100. Duffy, M.J.; Synnott, N.C.; McGowan, P.M.; Crown, J.; O’Connor, D.; Gallagher, W.M. P53 as a Target for the Treatment of Cancer. Cancer Treat. Rev. 2014, 40, 1153–1160. [Google Scholar] [CrossRef] [PubMed]
  101. Hashimoto, N.; Nagano, H.; Tanaka, T. The Role of Tumor Suppressor P53 in Metabolism and Energy Regulation, and Its Implication in Cancer and Lifestyle-Related Diseases. Endocr. J. 2019, 66, 485–496. [Google Scholar] [CrossRef]
  102. Olovnikov, I.A.; Kravchenko, J.E.; Chumakov, P.M. Homeostatic Functions of the P53 Tumor Suppressor: Regulation of Energy Metabolism and Antioxidant Defense. Semin. Cancer Biol. 2009, 19, 32–41. [Google Scholar] [CrossRef]
  103. Liu, J.; Zhang, C.; Hu, W.; Feng, Z. Tumor Suppressor P53 and Metabolism. J. Mol. Cell Biol. 2019, 11, 284–292. [Google Scholar] [CrossRef] [PubMed]
  104. Eriksson, M.; Ambroise, G.; Ouchida, A.T.; Lima Queiroz, A.; Smith, D.; Gimenez-Cassina, A.; Iwanicki, M.P.; Muller, P.A.; Norberg, E.; Vakifahmetoglu-Norberg, H. Effect of Mutant P53 Proteins on Glycolysis and Mitochondrial Metabolism. Mol. Cell Biol. 2017, 37, e00328-17. [Google Scholar] [CrossRef]
  105. Kim, J.; Yu, L.; Chen, W.; Xu, Y.; Wu, M.; Todorova, D.; Tang, Q.; Feng, B.; Jiang, L.; He, J.; et al. Wild-Type P53 Promotes Cancer Metabolic Switch by Inducing PUMA-Dependent Suppression of Oxidative Phosphorylation. Cancer Cell 2019, 35, 191–203.e8. [Google Scholar] [CrossRef]
  106. Zhuang, W.; Lian, G.; Huang, B.; Du, A.; Gong, J.; Xiao, G.; Xu, C.; Wang, H.; Xie, L. CPT1 Regulates the Proliferation of Pulmonary Artery Smooth Muscle Cells through the AMPK-P53-P21 Pathway in Pulmonary Arterial Hypertension. Mol. Cell Biochem. 2019, 455, 169–183. [Google Scholar] [CrossRef] [PubMed]
  107. Liu, J.; Zhang, C.; Hu, W.; Feng, Z. Tumor Suppressor P53 and Its Mutants in Cancer Metabolism. Cancer Lett. 2015, 356, 197–203. [Google Scholar] [CrossRef]
  108. Luck, K.; Kim, D.K.; Lambourne, L.; Spirohn, K.; Begg, B.E.; Bian, W.; Brignall, R.; Cafarelli, T.; Campos-Laborie, F.J.; Charloteaux, B.; et al. A Reference Map of the Human Binary Protein Interactome. Nature 2020, 580, 402–408. [Google Scholar] [CrossRef] [PubMed]
  109. Bader, M.S.; Meyer, S.C. JAK2 in Myeloproliferative Neoplasms: Still a Protagonist. Pharmaceuticals 2022, 15, 160. [Google Scholar] [CrossRef]
  110. Perner, F.; Perner, C.; Ernst, T.; Heidel, F.H. Roles of JAK2 in Aging, Inflammation, Hematopoiesis and Malignant Transformation. Cells 2019, 8, 854. [Google Scholar] [CrossRef] [PubMed]
  111. Barutcu, S.A.; Girnius, N.; Vernia, S.; Davis, R.J. Role of the MAPK/CJun NH2-Terminal Kinase Signaling Pathway in Starvation-Induced Autophagy. Autophagy 2018, 14, 1586–1595. [Google Scholar] [CrossRef]
  112. Li, D.; You, Y.; Bi, F.F.; Zhang, T.N.; Jiao, J.; Wang, T.R.; Zhou, Y.M.; Shen, Z.Q.; Wang, X.X.; Yang, Q. Autophagy Is Activated in the Ovarian Tissue of Polycystic Ovary Syndrome. Reproduction 2018, 155, 85–92. [Google Scholar] [CrossRef]
  113. Devis-Jauregui, L.; Eritja, N.; Davis, M.L.; Matias-Guiu, X.; Llobet-Navàs, D. Autophagy in the Physiological Endometrium and Cancer. Autophagy 2021, 17, 1077–1095. [Google Scholar] [CrossRef] [PubMed]
  114. Wörmann, S.M.; Song, L.; Ai, J.; Diakopoulos, K.N.; Kurkowski, M.U.; Görgülü, K.; Ruess, D.; Campbell, A.; Doglioni, C.; Jodrell, D.; et al. Loss of P53 Function Activates JAK2–STAT3 Signaling to Promote Pancreatic Tumor Growth, Stroma Modification, and Gemcitabine Resistance in Mice and Is Associated with Patient Survival. Gastroenterology 2016, 151, 180–193.E12. [Google Scholar] [CrossRef] [PubMed]
  115. Spurlock, C.F.; Tossberg, J.T.; Fuchs, H.A.; Olsen, N.J.; Aune, T.M. Methotrexate Increases Expression of Cell Cycle Checkpoint Genes via JNK Activation. Arthritis Rheum. 2012, 64, 1780–1789. [Google Scholar] [CrossRef]
  116. Yan, Y.; Long, T.; Su, Q.; Wang, Y.; Chen, K.; Yang, T.; Zhao, G.; Ma, Q.; Hu, X.; Liu, C.; et al. Cardiac ISL1-Interacting Protein, a Cardioprotective Factor, Inhibits the Transition from Cardiac Hypertrophy to Heart Failure. Front. Cardiovasc. Med. 2022, 9, 857049. [Google Scholar] [CrossRef] [PubMed]
Cells 13 01109 g001
Figure 1. Schematic representation of MLIP-associated stress response pathways in cellular homeostasis and disease. The central role of MLIP (muscle-enriched A-type lamin-interacting protein) in coordinating cellular responses to genotoxic and metabolic stress is shown, highlighting its potential implications in cancer.
Figure 1. Schematic representation of MLIP-associated stress response pathways in cellular homeostasis and disease. The central role of MLIP (muscle-enriched A-type lamin-interacting protein) in coordinating cellular responses to genotoxic and metabolic stress is shown, highlighting its potential implications in cancer.
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Cells 13 01109 g002
Figure 2. Regulatory interactions between MLIP and AMPK in cancer metabolism. This schematic illustrates the bidirectional regulatory relationship between muscle-enriched A-type lamin-interacting protein (MLIP) and AMP-activated protein kinase (AMPK). MLIP is depicted as acting on the fulcrum of AMPK action as an oncogene or tumor suppressor.
Figure 2. Regulatory interactions between MLIP and AMPK in cancer metabolism. This schematic illustrates the bidirectional regulatory relationship between muscle-enriched A-type lamin-interacting protein (MLIP) and AMP-activated protein kinase (AMPK). MLIP is depicted as acting on the fulcrum of AMPK action as an oncogene or tumor suppressor.
Cells 13 01109 g002
Cells 13 01109 g003
Figure 3. Comparative schematic of MLIP signaling pathways in physiological and pathological states. A comparative overview of the intracellular signaling pathways involving muscle-enriched A-type lamin-interacting protein (MLIP) in two states: physiological (left panel) and pathological (right panel). In the physiological state, MLIP negatively regulates AKT, leading to reduced mTOR activity and an increase in AMPK activity, depicted by solid black lines. These interactions suggest a role for MLIP in maintaining the cellular energy balance and potentially inhibiting cancer cell growth. In the pathological state (right panel), the loss of MLIP leads to increased AKT-mTOR activity, potentially promoting cell growth and proliferation. The altered signaling dynamics of MLIP in the pathological state underscore its potential as a regulatory switch in cancer metabolism and a target for therapeutic intervention. Figure created with BioRender.com. Reprinted with permission from Ref. [28]. Copyright 2015 Creative Commons CC-BY license.
Figure 3. Comparative schematic of MLIP signaling pathways in physiological and pathological states. A comparative overview of the intracellular signaling pathways involving muscle-enriched A-type lamin-interacting protein (MLIP) in two states: physiological (left panel) and pathological (right panel). In the physiological state, MLIP negatively regulates AKT, leading to reduced mTOR activity and an increase in AMPK activity, depicted by solid black lines. These interactions suggest a role for MLIP in maintaining the cellular energy balance and potentially inhibiting cancer cell growth. In the pathological state (right panel), the loss of MLIP leads to increased AKT-mTOR activity, potentially promoting cell growth and proliferation. The altered signaling dynamics of MLIP in the pathological state underscore its potential as a regulatory switch in cancer metabolism and a target for therapeutic intervention. Figure created with BioRender.com. Reprinted with permission from Ref. [28]. Copyright 2015 Creative Commons CC-BY license.
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Cells 13 01109 g004
Figure 4. Influence of MLIP on key signaling pathways and therapeutic interventions in cancer. This figure delineates the role of muscle-enriched A-type lamin-interacting protein (MLIP) in modulating critical signaling cascades involved in cancer pathophysiology. In the left panel, the MLIP interaction with the PI3K/AKT/mTOR pathway is illustrated, depicting potential points of therapeutic intervention with the listed drugs. The dashed lines represent indirect effects on downstream processes such as cell cycle arrest, DNA repair, senescence, and apoptosis, which are key cellular responses in cancer therapy. In the right panel, the absence of MLIP’s regulatory influence is shown to result in enhanced cell growth and division, as well as angiogenesis, contributing to tumor progression. The drugs targeting these pathways are grouped according to their mechanism of action, highlighting the potential for MLIP to serve as a pivotal point for therapeutic targeting in cancer treatment. Figure created with BioRender.com.
Figure 4. Influence of MLIP on key signaling pathways and therapeutic interventions in cancer. This figure delineates the role of muscle-enriched A-type lamin-interacting protein (MLIP) in modulating critical signaling cascades involved in cancer pathophysiology. In the left panel, the MLIP interaction with the PI3K/AKT/mTOR pathway is illustrated, depicting potential points of therapeutic intervention with the listed drugs. The dashed lines represent indirect effects on downstream processes such as cell cycle arrest, DNA repair, senescence, and apoptosis, which are key cellular responses in cancer therapy. In the right panel, the absence of MLIP’s regulatory influence is shown to result in enhanced cell growth and division, as well as angiogenesis, contributing to tumor progression. The drugs targeting these pathways are grouped according to their mechanism of action, highlighting the potential for MLIP to serve as a pivotal point for therapeutic targeting in cancer treatment. Figure created with BioRender.com.
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Table 1. Association of MLIP with various cancer types and clinical outcomes.
Table 1. Association of MLIP with various cancer types and clinical outcomes.
CancerStatusReference
Breast cancer1 out of 6 genes associated with breast cancer risk and recurrence-free survival[35]
Triple-negative breast cancerUpregulated in and associated with patient survival in triple-negative breast cancer[36]
Esophageal cancerOne of seven risk RNAs for esophageal cancer[37]
Table 2. Overview of targeted therapies acting on the PI3K/AKT/mTOR pathway in cancer.
Table 2. Overview of targeted therapies acting on the PI3K/AKT/mTOR pathway in cancer.
DrugMolecular TargetStatusReference
Idelalisib (Zydelig)PI3Krelapsed chronic lymphocytic leukemia (CLL), follicular lymphoma, and small lymphocytic lymphoma (SLL)[55]
Copanlisib (Aliqopa)PI3Krelapsed follicular lymphoma[56]
Duvelisib (Copiktra)PI3Krelapsed or refractory CLL, SLL, and follicular lymphoma[57]
Taselisib (GDC-0032)PI3Kinvestigational drug in clinical trials for various types of cancer, including breast cancer and lung cancer[58]
Alpelisib (Piqray)PI3KHR-positive, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer[59,60]
Pictilisib (GDC-0941)PI3Kinvestigational drug in clinical trials for various types of cancer, including breast cancer and non-small cell lung cancer[61]
Omipalisib (GSK2126458)PI3Kinvestigational drug in clinical trials for various types of cancer, including melanoma and pancreatic cancer[62]
Ipatasertib (GDC-0068)AKTinvestigational drug in clinical trials for various types of cancer, including breast cancer, prostate cancer, and ovarian cancer[63,64]
Capivaserib (AZD5363)AKTinvestigational drug in clinical trials for various types of cancer, including breast cancer, prostate cancer, and non-small cell lung cancer[65]
Miransertib (ARQ092)AKTinvestigational drug in clinical trials for various types of cancer, including endometrial cancer, solid tumors, and proteus syndrome[66]
Afuresertib (GSK2110183)AKTinvestigational drug in clinical trials for multiple myeloma and other hematologic malignancies[67]
Uprosertib (GSK2141795)AKTinvestigational drug in clinical trials for various types of cancer, including solid tumors and lymphomas[68]
MK-2206AKTinvestigational drug in clinical trials for various types of cancer, including breast cancer, colorectal cancer, and non-small cell lung cancer[69]
Everolimus (Afinitor, Zortress)mTORadvanced renal cell carcinoma (RCC), progressive neuroendocrine tumors of pancreatic origin (PNET), advanced hormone receptor-positive, HER2-negative breast cancer, renal angiomyolipoma with tuberous sclerosis complex (TSC), and subependymal giant cell astrocytoma (SEGA) associated with TSC[70,71]
Temsirolimus (Torisel)mTORadvanced renal cell carcinoma (RCC)[72]
Sirolimus (Rapamune)mTORpotential anti-cancer properties in certain cancers, such as TSC-associated lymphangioleiomyomatosis (LAM)[73]
Ridaforolimus (AP23573, MK-8669)mTORinvestigational drug in clinical trials for various types of cancer, including sarcomas, endometrial cancer, and other solid tumors[74]
Sapanisertib (INK128, TAK-228)mTORinvestigational drug in clinical trials for various types of cancer, including breast cancer, renal cell carcinoma, and non-Hodgkin’s lymphoma[75]
AZD2014 (Vistusertib)mTORinvestigational drug in clinical trials for various types of cancer, including endometrial cancer, breast cancer, and non-small cell lung cancer[76]
Dactolisib (BEZ235)dual PI3K/mTORpreclinical and early-phase clinical trials for various types of solid tumors, including breast, prostate, and renal cell carcinoma[77]
Apitolisib (GDC-0980)dual PI3K/mTORearly-phase clinical trials for various types of solid tumors, including colorectal, breast, and prostate cancer[78,79]
Bimiralisib (PQR309)dual PI3K/mTORearly-phase clinical trials for various types of solid tumors and lymphomas[80]
Omipalisib (GSK2126458)dual PI3K/mTORearly-phase clinical trials for various types of solid tumors and hematologic malignancies[62,81]
Gedatolisib (PF-05212384)dual PI3K/mTORearly-phase clinical trials for various types of solid tumors and hematologic malignancies[82]
Vistusertib (AZD2014)dual PI3K/mTOR early-phase clinical trials for various types of solid tumors and hematologic malignancies[83]
Serabelisib (INK1117, MLN0128, TAK-228)dual PI3K/mTORearly-phase clinical trials for various types of solid tumors and hematologic malignancies[84,85]
Table 3. Functional roles of FOXO transcription factors in cell Biology and cancer.
Table 3. Functional roles of FOXO transcription factors in cell Biology and cancer.
FOXO TypeRole in Cell BiologyRole in CancerTypes of TumorsReferences
FOXO1Regulation of gluconeogenesis, cell proliferation, apoptosis, metabolism, inflammation, differentiation, and stress resistance. Global deletion causes embryonic cell death due to incomplete vascular development.Tumor suppressor, regulation of cell cycle arrest, apoptosis, and DNA repairLymphoma, soft tissue sarcoma, acute myeloid leukemia (AML), breast cancer[90]
FOXO2Involved in multiple important biological processes, such as cell cycle arrest, DNA repair, apoptosis, glucose metabolism, aging, and autophagy.Tumor suppressor, regulation of cell cycle arrest, apoptosis, and DNA repairNot specified[90]
FOXO3Affects lymph proliferation, widespread organ inflammation. Expression found in most tissues, including lymphocytes and myeloid cells.Tumor suppressor, regulation of cell cycle arrest, apoptosis, and DNA repairNeuroblastoma, breast cancer, colorectal cancer, glioblastoma, pancreatic ductal adenocarcinoma[90]
FOXO4Required for stem cell function in multiple tissues, including the maintenance of hematopoietic, neural, and muscle stem cell pools.Tumor suppressor, regulation of cell cycle arrest and apoptosisNot specified[90]
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Hamwi, M.N.; Elsayed, E.; Dabash, H.; Abuawad, A.; Aweer, N.A.; Al Zeir, F.; Pedersen, S.; Al-Mansoori, L.; Burgon, P.G. MLIP and Its Potential Influence on Key Oncogenic Pathways. Cells 2024, 13, 1109. https://doi.org/10.3390/cells13131109

AMA Style

Hamwi MN, Elsayed E, Dabash H, Abuawad A, Aweer NA, Al Zeir F, Pedersen S, Al-Mansoori L, Burgon PG. MLIP and Its Potential Influence on Key Oncogenic Pathways. Cells. 2024; 13(13):1109. https://doi.org/10.3390/cells13131109

Chicago/Turabian Style

Hamwi, Mahmoud N., Engy Elsayed, Hanan Dabash, Amani Abuawad, Noor A. Aweer, Faissal Al Zeir, Shona Pedersen, Layla Al-Mansoori, and Patrick G. Burgon. 2024. "MLIP and Its Potential Influence on Key Oncogenic Pathways" Cells 13, no. 13: 1109. https://doi.org/10.3390/cells13131109

APA Style

Hamwi, M. N., Elsayed, E., Dabash, H., Abuawad, A., Aweer, N. A., Al Zeir, F., Pedersen, S., Al-Mansoori, L., & Burgon, P. G. (2024). MLIP and Its Potential Influence on Key Oncogenic Pathways. Cells, 13(13), 1109. https://doi.org/10.3390/cells13131109

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