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Targeting PI3K/AKT/mTOR Signaling Pathway in Cancer
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Targeting PI3K/AKT/mTOR Signaling Pathway in Cancer

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (20 March 2023) | Viewed by 26264

Special Issue Editors

Dr. Daniela Miricescu

E-Mail Website
Guest Editor
Department of Biochemistry, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
Interests: PI3K/AKT/mTOR; oxidative stress; breast cancer; burns; colorectal cancer; PLGA nanoparticles; platelet rich plasma
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Maria Greabu

E-Mail Website
Guest Editor
Department of Biochemistry, Faculty of Dentistry, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania
Interests: dental biochemistry; oxidative stress in systemic and oral diseases; salivary biomarkers; AKT/mTOR signaling pathway; molecular and biochemical aspects in burns
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway regulates the cell proliferation, growth, survival, invasion, migration, glucose metabolism, apoptosis, and motility of cells. Growth factors, hormones, mitogens, cytokines, and chemokines activate this molecular pathway after binding to receptor tyrosine kinases (RTKs) or G protein-coupled receptors (GPCP). PI3K/AKT/mTOR dysregulation is frequently associated with genetic/epigenetic alterations in a wide variety of human cancers, including breast, skin, lung, gastric, colorectal, renal, ovarian, oral, and prostate. The inactivation of phosphatase and tensin homolog (PTEN) and/or activation of PIK3CA and RTKs mutations are frequently reported in cancer, contributing to tumor growth and survival. Thus, inhibitors have been developed to block the key players, PI3K/ AKT/mTOR, some of them already approved by the FDA, with promising results in clinical trials. PI3K/AKT/mTOR pathway inhibition may be a new method of improving cancer patients’ survival rate.

In this Special Issue, emphasis will be put on the molecular facets of the relationship between PI3K/AKT/mTOR and cancer. Original research (molecular mechanisms and preclinical) and review articles are welcome.

Dr. Daniela Miricescu
Prof. Dr. Maria Greabu
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

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Keywords

  • growth factors
  • cytokines
  • hormones
  • signaling pathway dysregulation
  • PI3K/AKT/mTOR mutations
  • malignancy
  • clinical inhibitors

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Published Papers (5 papers)

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Research

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19 pages, 3972 KiB  
Article
Modulating p-AMPK/mTOR Pathway of Mitochondrial Dysfunction Caused by MTERF1 Abnormal Expression in Colorectal Cancer Cells
by Qianqian Liu, Longlong Zhang, Yayan Zou, Ying Tao, Bing Wang, Bin Li, Ruai Liu, Boyong Wang, Lei Ding, Qinghua Cui, Jie Lin, Bingyu Mao, Wei Xiong and Min Yu
Int. J. Mol. Sci. 2022, 23(20), 12354; https://doi.org/10.3390/ijms232012354 - 15 Oct 2022
Cited by 10 | Viewed by 3431
Abstract
Human mitochondrial transcription termination factor 1 (MTERF1) has been demonstrated to play an important role in mitochondrial gene expression regulation. However, the molecular mechanism of MTERF1 in colorectal cancer (CRC) remains largely unknown. Here, we found that MTERF1 expression was significantly increased in [...] Read more.
Human mitochondrial transcription termination factor 1 (MTERF1) has been demonstrated to play an important role in mitochondrial gene expression regulation. However, the molecular mechanism of MTERF1 in colorectal cancer (CRC) remains largely unknown. Here, we found that MTERF1 expression was significantly increased in colon cancer tissues compared with normal colorectal tissue by Western blotting, immunohistochemistry, and tissue microarrays (TMA). Overexpression of MTERF1 in the HT29 cell promoted cell proliferation, migration, invasion, and xenograft tumor formation, whereas knockdown of MTERF1 in HCT116 cells appeared to be the opposite phenotype to HT29 cells. Furthermore, MTERF1 can increase mitochondrial DNA (mtDNA) replication, transcription, and protein synthesis in colorectal cancer cells; increase ATP levels, the mitochondrial crista density, mitochondrial membrane potential, and oxygen consumption rate (OCR); and reduce the ROS production in colorectal cancer cells, thereby enhancing mitochondrial oxidative phosphorylation (OXPHOS) activity. Mechanistically, we revealed that MTERF1 regulates the AMPK/mTOR signaling pathway in cancerous cell lines, and we also confirmed the involvement of the AMPK/mTOR signaling pathway in both xenograft tumor tissues and colorectal cancer tissues. In summary, our data reveal an oncogenic role of MTERF1 in CRC progression, indicating that MTERF1 may represent a new therapeutic target in the future. Full article
(This article belongs to the Special Issue Targeting PI3K/AKT/mTOR Signaling Pathway in Cancer)
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Review

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29 pages, 826 KiB  
Review
PI3K/AKT/mTOR Dysregulation and Reprogramming Metabolic Pathways in Renal Cancer: Crosstalk with the VHL/HIF Axis
by Silviu Constantin Badoiu, Maria Greabu, Daniela Miricescu, Iulia-Ioana Stanescu-Spinu, Radu Ilinca, Daniela Gabriela Balan, Andra-Elena Balcangiu-Stroescu, Doina-Andrada Mihai, Ileana Adela Vacaroiu, Constantin Stefani and Viorel Jinga
Int. J. Mol. Sci. 2023, 24(9), 8391; https://doi.org/10.3390/ijms24098391 - 7 May 2023
Cited by 31 | Viewed by 5895
Abstract
Renal cell carcinoma (RCC) represents 85–95% of kidney cancers and is the most frequent type of renal cancer in adult patients. It accounts for 3% of all cancer cases and is in 7th place among the most frequent histological types of cancer. Clear [...] Read more.
Renal cell carcinoma (RCC) represents 85–95% of kidney cancers and is the most frequent type of renal cancer in adult patients. It accounts for 3% of all cancer cases and is in 7th place among the most frequent histological types of cancer. Clear cell renal cell carcinoma (ccRCC), accounts for 75% of RCCs and has the most kidney cancer-related deaths. One-third of the patients with ccRCC develop metastases. Renal cancer presents cellular alterations in sugars, lipids, amino acids, and nucleic acid metabolism. RCC is characterized by several metabolic dysregulations including oxygen sensing (VHL/HIF pathway), glucose transporters (GLUT 1 and GLUT 4) energy sensing, and energy nutrient sensing cascade. Metabolic reprogramming represents an important characteristic of the cancer cells to survive in nutrient and oxygen-deprived environments, to proliferate and metastasize in different body sites. The phosphoinositide 3-kinase-AKT-mammalian target of the rapamycin (PI3K/AKT/mTOR) signaling pathway is usually dysregulated in various cancer types including renal cancer. This molecular pathway is frequently correlated with tumor growth and survival. The main aim of this review is to present renal cancer types, dysregulation of PI3K/AKT/mTOR signaling pathway members, crosstalk with VHL/HIF axis, and carbohydrates, lipids, and amino acid alterations. Full article
(This article belongs to the Special Issue Targeting PI3K/AKT/mTOR Signaling Pathway in Cancer)
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25 pages, 1989 KiB  
Review
Targeting PI3K/AKT/mTOR Signaling Pathway in Pancreatic Cancer: From Molecular to Clinical Aspects
by Silviu Stanciu, Florentina Ionita-Radu, Constantin Stefani, Daniela Miricescu, Iulia-Ioana Stanescu-Spinu, Maria Greabu, Alexandra Ripszky Totan and Mariana Jinga
Int. J. Mol. Sci. 2022, 23(17), 10132; https://doi.org/10.3390/ijms231710132 - 4 Sep 2022
Cited by 72 | Viewed by 6593
Abstract
Although pancreatic cancer (PC) was considered in the past an orphan cancer type due to its low incidence, it may become in the future one of the leading causes of cancer death. Pancreatic ductal adenocarcinoma (PDAC) is the most frequent type of PC, [...] Read more.
Although pancreatic cancer (PC) was considered in the past an orphan cancer type due to its low incidence, it may become in the future one of the leading causes of cancer death. Pancreatic ductal adenocarcinoma (PDAC) is the most frequent type of PC, being a highly aggressive malignancy and having a 5-year survival rate of less than 10%. Non-modifiable (family history, age, genetic susceptibility) and modifiable (smoking, alcohol, acute and chronic pancreatitis, diabetes mellitus, intestinal microbiota) risk factors are involved in PC pathogenesis. Chronic inflammation induced by various factors plays crucial roles in PC development from initiation to metastasis. In multiple malignant conditions such as PC, cytokines, chemokines, and growth factors activate the class I phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) (PI3K/AKT/mTOR) signaling pathway, which plays key roles in cell growth, survival, proliferation, metabolism, and motility. Currently, mTOR, AKT, and PI3K inhibitors are used in clinical studies. Moreover, PI3K/mTOR dual inhibitors are being tested in vitro and in vivo with promising results for PC patients. The main aim of this review is to present PC incidence, risk factors, tumor microenvironment development, and PI3K/AKT/mTOR dysregulation and inhibitors used in clinical, in vivo, and in vitro studies. Full article
(This article belongs to the Special Issue Targeting PI3K/AKT/mTOR Signaling Pathway in Cancer)
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23 pages, 1520 KiB  
Review
Intracellular Pathways and Mechanisms of Colored Secondary Metabolites in Cancer Therapy
by Ani-Simona Sevastre, Elena Victoria Manea, Oana Stefana Popescu, Daniela Elise Tache, Suzana Danoiu, Veronica Sfredel, Ligia Gabriela Tataranu and Anica Dricu
Int. J. Mol. Sci. 2022, 23(17), 9943; https://doi.org/10.3390/ijms23179943 - 1 Sep 2022
Cited by 8 | Viewed by 2843
Abstract
Despite the great advancements made in cancer treatment, there are still many unsatisfied aspects, such as the wide palette of side effects and the drug resistance. There is an obvious increasing scientific attention towards nature and what it can offer the human race. [...] Read more.
Despite the great advancements made in cancer treatment, there are still many unsatisfied aspects, such as the wide palette of side effects and the drug resistance. There is an obvious increasing scientific attention towards nature and what it can offer the human race. Natural products can be used to treat many diseases, of which some plant products are currently used to treat cancer. Plants produce secondary metabolites for their signaling mechanisms and natural defense. A variety of plant-derived products have shown promising anticancer properties in vitro and in vivo. Rather than recreating the natural production environment, ongoing studies are currently setting various strategies to significantly manipulate the quantity of anticancer molecules in plants. This review focuses on the recently studied secondary metabolite agents that have shown promising anticancer activity, outlining their potential mechanisms of action and pathways. Full article
(This article belongs to the Special Issue Targeting PI3K/AKT/mTOR Signaling Pathway in Cancer)
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15 pages, 1052 KiB  
Review
Immunomodulatory Properties of PI3K/AKT/mTOR and MAPK/MEK/ERK Inhibition Augment Response to Immune Checkpoint Blockade in Melanoma and Triple-Negative Breast Cancer
by Zhizhu Zhang, Ann Richmond and Chi Yan
Int. J. Mol. Sci. 2022, 23(13), 7353; https://doi.org/10.3390/ijms23137353 - 1 Jul 2022
Cited by 47 | Viewed by 6265
Abstract
Hyperactivation of PI3K/AKT/mTOR and MAPK/MEK/ERK signaling pathways is commonly observed in many cancers, including triple-negative breast cancer (TNBC) and melanoma. Moreover, the compensatory upregulation of the MAPK/MEK/ERK pathway has been associated with therapeutic resistance to targeted inhibition of the PI3K/AKT/mTOR pathway, and vice [...] Read more.
Hyperactivation of PI3K/AKT/mTOR and MAPK/MEK/ERK signaling pathways is commonly observed in many cancers, including triple-negative breast cancer (TNBC) and melanoma. Moreover, the compensatory upregulation of the MAPK/MEK/ERK pathway has been associated with therapeutic resistance to targeted inhibition of the PI3K/AKT/mTOR pathway, and vice versa. The immune-modulatory effects of both PI3K and MAPK inhibition suggest that inhibition of these pathways might enhance response to immune checkpoint inhibitors (ICIs). ICIs have become the standard-of-care for metastatic melanoma and are recently an option for TNBC when combined with chemotherapy, but alternative options are needed when resistance develops. In this review, we present the current mechanistic understandings, along with preclinical and clinical evidence, that outline the efficacy and safety profile of combinatorial or sequential treatments with PI3K inhibitors, MAPK inhibitors, and ICIs for treatment of malignant melanoma and metastatic TNBC. This approach may present a potential strategy to overcome resistance in patients who are a candidate for ICI therapy with tumors harboring either or both of these pathway-associated mutations. Full article
(This article belongs to the Special Issue Targeting PI3K/AKT/mTOR Signaling Pathway in Cancer)
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