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Review

The Role of MARCKS in Metastasis and Treatment Resistance of Solid Tumors

by
Chun-Lung Chiu
1,
Hongjuan Zhao
1,
Ching-Hsien Chen
2,3,
Reen Wu
2,4,* and
James D. Brooks
1,*
1
Department of Urology, School of Medicine, Stanford University, Stanford, CA 94304, USA
2
Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, Center for Comparative Respiratory Biology and Medicine, School of Medicine, University of California Davis, Davis, CA 95616, USA
3
Department of Internal Medicine, Division of Nephrology, University of California Davis, Davis, CA 95616, USA
4
Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California Davis, Davis, CA 95616, USA
*
Authors to whom correspondence should be addressed.
Cancers 2022, 14(19), 4925; https://doi.org/10.3390/cancers14194925
Submission received: 19 September 2022 / Revised: 5 October 2022 / Accepted: 7 October 2022 / Published: 8 October 2022
(This article belongs to the Section Tumor Microenvironment)
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Abstract

:

Simple Summary

Cancer metastasis is a critical event in the progression of solid tumors and is invariably associated with adverse outcomes and mortality. Understanding novel mechanisms or molecules that promote cancer metastasis will facilitate the development of new strategies for cancer treatment. Recently, MARCKS has been studied extensively in several cancers and has been implicated in tumor progression and metastasis. This review summarizes recent advances in the understanding of MARCKS on cancer metastasis, stemness, and therapeutic resistance and provides prospects on targeting MARCKS therapeutically. Specifically, we review the molecular mechanisms and multiple signaling pathways by which MARCKS contributes to the progression and metastasis in solid tumors.

Abstract

The myristoylated alanine-rich C-kinase substrate (MARCKS) is a membrane-associated protein kinase C (PKC) substrate ubiquitously expressed in eukaryotic cells. MARCKS plays important roles in multiple cellular processes, including cell adhesion and motility, mucin secretion, exocytosis, and inflammatory response. Aberrant MARCKS signaling has been observed in the development and progression of multiple cancer types. In addition, MARCKS facilitates cancer metastasis through modulating cancer cell migration and invasion. Moreover, MARCKS contributes to treatment resistance, likely by promoting cancer stem cell renewal as well as immunosuppression. In this review, we describe MARCKS protein structure, cellular localization, and biological functions. We then discuss the role of MARCKS in cancer metastasis as well as its mechanisms of action in solid tumors. Finally, we review recent advances in targeting MARCKS as a new therapeutic strategy in cancer management.

1. Introduction

Metastasis, defined by disseminated cancer cells at sites distant from the primary tumor, is the principal cause of cancer death, as shown by the stark differences in 5-year survival rates for localized compared to metastatic disease [1]. Studies have shown that large numbers of disseminated tumor cells are released from the primary tumor in the early stages of cancer growth. However, only a small fraction of these cells are able to colonize distant foreign tissue sites, adapt to a relatively inhospitable microenvironment and then progress from micro- to macro-metastatic disease [2]. These metastasis-initiating cells often possess stem-like properties, allowing them to undergo epithelial-mesenchymal transitions, enter slow-cycling states for dormancy, evade immune surveillance, establish supportive interactions with organ-specific niches, and co-opt systemic factors for growth and resistance to anticancer therapies [3,4,5]. A growing body of evidence implicates the myristoylated alanine-rich C-kinase substrate (MARCKS), and the highly homologous MARCKS-like protein 1 (MARCKSL1) in cancer migration and metastasis. Both MARCKS and MARCKSL1 are activated by phosphorylation, suggesting that MARCKS-targeted therapies could be used to treat cancer metastasis [6,7,8,9,10,11,12,13]. Our understanding of the molecular mechanisms underlying the role of MARCKS in promoting cancer metastasis and therapeutic resistance is still incomplete; however, much progress has been made [14,15]. In hematological malignancies, MARCKS expression and phosphorylation have been implicated in treatment resistance and are associated with disease-specific mortality [16]. However, whether increased MARCKS confers treatment resistance in solid tumors remains unclear. In this review, we discuss the structure, localization, and function of MARCKS, describe the role and mechanisms of MARCKS in potentiating cancer metastasis and review whether MARCKS contributes to treatment resistance in solid tumors.

2. Protein Structure and Cellular Localization of MARCKS

MARCKS, an actin filament crosslinking protein, has a 32 kDa molecular weight that was originally identified as an 87 kDa protein substrate for Protein Kinase C (PKC) due to its anomalous molecular behavior and is ubiquitously expressed in eukaryotic cells [16,17,18]. This rod-shaped protein contains three distinct evolutionarily conserved regions: the N-terminal myristoylated domain (NMD), the multiple homology 2 domain (MH2), and the phosphorylation site domain (PSD) (also known as effector domain (ED)) [19]. The NMD recognized by N-myristoyl transferase mediates the insertion of the myristoyl moiety into the hydrophobic lipid bilayer of the plasma membrane [20], while the MH2 domain interacts with actin and contains a potential dimerization motif [18]. The highly positively charged PSD is crucial for the functionality of MARCKS and the source of its ability to electrostatically bind to phosphatidylinositol bisphosphate (PIP2), a docking site on the inner leaflet of the plasma membrane and a direct activator of numerous membrane proteins [21]. Phosphorylation by PKC within MARCKS PSD at Ser159, Ser163, and Ser170 directly or through RhoA/ROCK at Ser159 [22] or calcium-dependent calmodulin-binding reduces MARCKS binding to PIP2 and leads to MARCKS release from the plasma membrane into the cytoplasm, where it acts as a key regulatory protein [23].

3. Biological Functions of MARCKS

The biological functions of MARCKS primarily depend on its phosphorylation-dephosphorylation status, which in turn determines its membrane vs. cytosolic localization where it interacts with its two main binding partners, actin and PIP2 [14,15]. At the plasma membrane, phosphorylated MARCKS directly binds to and cross-links filamentous actin to modulate cytoskeletal structure in critical biological processes such as wound healing, morphogenesis, embryogenesis, and metastasis [24,25]. In addition, MARCKS has been proposed to link secretory granules to the cytoskeletal actin and myosin for exocytosis [26]. Moreover, MARCKS sequesters PIP2 at lipid rafts in the cell membrane in various cell types, including neutrophils [27,28], macrophages [29], fibroblasts [30], and hepatic stellate cells [31], to regulate cell motility and chemotaxis. By regulating PIP2 and its downstream secondary messengers such as inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) [32,33], MARCKS indirectly modulates multiple cellular processes, including cell migration, membrane trafficking, mitosis, vesicular trafficking, receptor endocytosis, exocytosis, and cytoskeletal reorganization [34]. Finally, MARCKS mediates the inflammatory response through the regulation of cell migration and inflammatory cytokines in macrophages and neutrophils [19,35,36,37].

4. MARCKS in Cancer Metastasis

MARCKS signaling has been implicated in promoting cancer progression and metastasis in several solid malignancies through the interactions of its highly conserved effector domain with other crucial proteins such as actin [38], PKC, and AKT [14]. Since MARCKS was first implicated in solid tumors [39], the number of publications has grown rapidly, and the ratio of solid tumor-related publications to total MARCKS publications has increased dramatically from 1989 to 2021 (Figure 1).
In lung cancer, MARCKS phosphorylation is correlated with advanced stage and lymph node metastasis and predicts shorter survival [40,41]. Elevated MARCKS phosphorylation enhances migration and invasion of lung cancer cells in vitro and metastasis in vivo [9], while a MARCKS-inhibiting peptide attenuates cell growth, migration, and invasion and reduces metastasis in both subcutaneous and orthotopic xenograft models, likely through modulating NF-κB signaling [42,43,44]. In addition, an inhaled MARCKS inhibitor, BIO-11006, demonstrated an improvement of the overall response rate in patients [45]. In addition, MARCKS overexpression has been observed in aggressive subtypes of breast cancer, i.e., basal-like and HER2 subtypes [46], and is also associated with tumor grade, presence of metastases, and poor survival in male breast cancer and inflammatory breast cancer [47,48,49], possibly through increased MARCKS binding to Tob which decreases binding of Tob with ErbB2 and subsequent activation of ErbB2 signaling [50,51]. In renal cell carcinoma (RCC), MARCKS phosphorylation is positively correlated with tumor grade, and increased MARCKS expression promotes tumor growth and angiogenesis in vivo in an RCC xenograft model [52]. Suppression of MARCKS by genetic and pharmacologic approaches in high-grade RCC cell lines in vitro decreases cell proliferation and migration and suppresses angiogenesis in vivo by downregulating the AKT/mTOR pathway and HIF-target genes, notably vascular endothelial growth factor-A [52]. MARCKS phosphorylation also promotes cell migration and invasion in vitro and predicts shorter survival times in cholangiocarcinoma patients [53]. Moreover, knockdown of MARCKS in human hepatocellular carcinoma cells in vitro reduces cell migration and invasion, but not cell proliferation [54]. Finally, MARCKS phosphorylation drives motility and invasiveness of melanoma cells of both murine and human origin. Inhibition of MARCKS phosphorylation with a MARCKS-inhibitory peptide abolishes WNT5A-mediated melanoma cell invasion [8,25], suggesting that MARCKS is a crucial promoter of metastasis in melanoma and a candidate anti-metastatic target in melanoma patients.
MARCKS expression and phosphorylation are not universally associated with promoting cancer progression in other solid tumors. For instance, in a mouse colon cancer model, MARCKS depletion reduces motility and invasion in vitro and significantly inhibits metastases in a syngeneic model of colon metastasis in vivo [55]. However, the inactivation of MARCKS is commonly observed in human colon cancers and associated with adverse patient outcomes, suggesting that MARCKS acts as a suppressor of progression in human colorectal cancer [56]. In glioblastoma multiforme (GBM), down-regulation of MARCKS expression with small interfering RNA in cells constitutively expressing EGFRvIII, a mediator of MARCKS phosphorylation, leads to decreased cell adhesion, spreading, and invasion in vitro [57]. However, MARCKS protein expression levels are inversely correlated with GBM proliferation and intracranial xenograft growth rates in vivo, and high expression levels are associated with improved patient survival [58]. These seemingly inconsistent results could be due to the critical role of phosphorylation in the regulation of MARCKS, such that protein expression levels alone fail to correlate with important clinical and biological outcomes. It is well established that phosphorylation of MARCKS, and not MARCKS expression levels, drives cancer cell proliferation and motility. High protein levels of non-phosphorylated MARCKS could attenuate the metastatic phenotype by sequestration of PIP2 at the cell membrane, thereby suppressing PIP2-mediated signaling through downstream pathways such as PI3K/AKT and PLD [15].
Conflicting results on the role of MARCKS in cancer progression and metastasis have also been observed in prostate cancer. Dorris et al. showed that knockdown of MARCKS in PC3 cells significantly decreases migration and invasion through downregulation of MMP9 gene expression [6], suggesting that MARCKS promotes prostate cancer metastasis. In agreement with these findings, increased expression of MARCKS is associated with recurrence following surgery for clinically localized prostate cancers [6]. However, Li et al. reported that upregulation of MARCKS protein expression by knockdown of miR-21, a direct regulator of MARCKS, inhibits cell motility and invasion in PC3 cells [59]. In addition, two independent studies demonstrated that targeted knockdown of MARCKSL1, a homologue of MARCKS, in PC3 cells promotes cell migration in vitro [13,60]. While the inhibitory effects of miR-21 knockdown could be due to downstream targets other than MARCKS, they could also be caused by sequestration of PIP2 by unphosphorylated MARCKS, leading to suppression of PIP2-mediated signaling. Indeed, Björkblom et al. showed that dephosphorylated MARCKSL1 increases cell migration, while MARCKSL1 phosphorylated by JNK inhibits cell migration by bundling and stabilizing F-actin [13,38]. Finally, a recent proteomic analysis of urinary and tissue-exudative extracellular vesicles has demonstrated that MARCKS and MARCKSL1 are significantly upregulated in bladder cancer patients [61], and phorbol 12-myristate 13-acetate (PMA)-induced hyperphosphorylation of MARCKS inhibits invasiveness in bladder cancer cells by modulating the cytoskeletal structure [62].
Taken together, the majority of the evidence points to a promoting role of MARCKS in cancer metastasis through multiple signaling pathways (Figure 2) in most solid tumors, indicating MARCKS may serve as a potential therapeutic target to tackle metastatic disease. Further studies are needed to define the role of MARCKS in cancer metastasis in cancers where inconsistent results have been observed. Table 1 summaries the roles of MARCKS and MARCKSL1 in different solid tumors.

5. MARCKS in Cancer Stemness

MARCKS and MARCKL1 are both substrates of PKC [12], and PKC is an important signalling pathway for stemness, self-renewal, and tumorigenesis [64,65]. For instance, in lung tumor-initiating cells (TICs), protein kinase C iota (PKCiota) is required for oncogene-induced tumor cell expansion and transformation [66], likely through phosphorylation of the ELF3 transcription factor and induced expression of NOTCH3, resulting in cancer stemness and promoting lung cancer development [67]. In breast cancer, protein kinase C α (PKCα) activation leads to the formation of cancer stem cells from non-stem cells, and a PKCα inhibitor depletes stem-like cells [68]. Tobacco smoke-induced phospho-MARCKS upregulates the expression of pro-inflammatory cytokines, causes the epithelial-to-mesenchymal transition and induces stem-like properties in smoke-related lung cancer, which can be reversed by a MARCKS-inhibiting peptide [44]. Furthermore, MARCKS transcript levels are upregulated in chronic myelogenous leukemia quiescent stem/progenitor cells [69], and secreted MARCKS protein has been identified in pancreatic cancer stem cells [70]. Finally, increased levels of MARCKS and MARCKSL1 protein mediated by a long noncoding RNA Zic family member 2 (lncZic2) and transcriptional factor BRG1 were detected during hepatocellular carcinogenesis and hepatic TIC self-renewal [71]. This association suggests that the lncZic2–BRG1–MARCKS/MARCKSL1 signaling cascade might be a potential pathway to target to eliminate hepatic TICs.

6. MARCKS in Cancer Therapeutic Resistance

The development of resistance to cancer therapies, including conventional chemotherapeutic agents and radiation, is one of the main causes of cancer relapse leading to mortality [72]. Substantial evidence implicates cancer stem cells and acquisition of a cancer stem cell phenotype in driving therapy resistance [73,74,75]. Given the growing body of evidence demonstrating that MARCKS plays an important role in cancer stemness, it is possible that MARCKS expression and phosphorylation play an important role in therapeutic resistance. Indeed, several studies have demonstrated that MARCKS expression levels are correlated with response to radiation and chemotherapy in multiple cancers. MARCKS is upregulated in oxaliplatin-resistant pancreatic cancer cells and tamoxifen-resistant breast cancer cells compared to cells sensitive to those therapies [46,76]. Moreover, treatment with a MARCKS-inhibiting peptide suppresses lung cancer growth and metastasis in vivo and enhances the sensitivity of erlotinib in lung cancer cells, particularly those tumors with sustained activation of phosphoinositide 3-kinase/AKT signaling [63]. Finally, inhibition of MARCKS phosphorylation sensitizes colon cancer cells to doxorubicin or 5-FU-based chemotherapy by decreasing ATP-binding-cassette transporter family member ABCB1 internalization [77], thereby reducing ABCB1 activity, a major cause of chemotherapy resistance in cancer [78,79]. These studies demonstrated the potential of targeting MARCKS signaling as a novel therapeutic strategy to inhibit cancer stemness and overcome resistance to cancer therapies. However, it is not clear that inhibition of MARCKS could circumvent therapeutic resistance in all cancers. In glioblastoma multiforme (GBM) model systems, knockdown of MARCKS is associated with increased resistance to radiation by increasing DNA repair in PTEN-null GBM cells in vitro and orthotopic xenografts in vivo [58,80]. Additional studies will be necessary to characterize the roles and mechanisms of MARCKS in therapeutic resistance across cancer types.

7. Targeting MARCKS as a New Therapeutic Strategy

MARCKS function depends on its NMD and PSD or ED, which are required for its membrane localization and phosphorylation; therefore, peptides targeting these domains have been developed to inhibit its function in various cancers. MANS peptide that targets NMD has been shown to reduce lung cancer metastasis while leaving tumor growth unaffected in vivo [42]. In addition, treatment of breast cancer xenografts with MANS peptide sensitizes cancer cells to paclitaxel and decreases angiogenesis/metastasis of cancer cells by reducing phospho-MARCKS levels [49].
Moreover, MANS peptide is able to suppress WNT5A-induced melanoma cell invasion in vitro by inhibiting MARCKS phosphorylation without affecting MARCKS expression [8]. BIO-11006, an analog of the MANS peptide containing the active site of MANS (the first 10 amino acids), is superior to MANS as an anti-cancer agent in that it is smaller in size and more soluble, while maintaining identical MARCKS-inhibitory actions [81]. In a phase II clinical trial of late-stage non-small cell lung cancer, BIO-11006 significantly increased the overall response rate of patients to standard-of-care chemotherapy by decreasing MARCKS phosphorylation [45].
Interestingly, studies have shown that peptides targeting PSD are more efficacious as anti-cancer therapeutics than peptides targeting the myristoylation domain. MPS peptide, a 25-mer peptide targeting PSD, not only suppresses lung cancer metastasis, but also inhibits tumor growth in vivo by decreasing levels of phospho-MARCKS, phosphatidylinositol (3,4,5)-triphosphate, and AKT activity [63]. In addition, MPS peptide suppresses smoke-mediated NF-κB signalling activity, pro-inflammatory cytokine expression, aggressiveness and stemness of lung cancer cells in vitro [44]. In kidney cancer, MPS peptide reduces cell proliferation, migration, and survival and sensitizes cells to regorafenib treatment through inhibiting the AKT and mTOR pathways [52]. In multiple myloma (MM), MPS peptide displays dose-dependent cytotoxicity toward bortezomib-resistant MM cells as a single agent both in vitro and in a xenograft model of MM and sensitizes these cells to bortezomib in combination therapy [82]. In GBM, MARCKS ED peptide produces rapid cytotoxicity through a GBM-specific mechanism involving plasma membrane targeting and intracellular calcium accumulation [83]. Finally, a highly basic 24-amino-acid peptide targeting MARCKSL1 ED was shown to inhibit MARCKSL1 hydrolysis. When synthesized together with an N-terminal HIV-1 Tat transduction domain (TD), MARCKSL1 ED peptide efficiently enters both macrophages and parasites in a Tat TD-dependent manner, suggesting such a strategy may be useful in enhancing cell permeability of MARCKS peptide inhibitors [84].

8. Conclusions

MARCKS, a major substrate of PKC, plays a critical role in cancer development and progression and is strongly implicated in cancer metastasis, cancer stemness, and therapeutic resistance (Figure 2). Phosphorylation of MARCKS by PKC leads to MARCKS protein translocation from the plasma membrane to cytosol, where it functions to modulate the cytoskeletal structure and promote cell migration, invasion, and metastasis in the majority of solid tumors. Conflicting results in a few cancer types on the contribution of MARCKS expression levels to metastasis, clinical outcomes, and therapeutic resistance are likely explained by differences in MARCKS phosphorylation, which is primarily responsible for MARCKS regulation and its cellular functions. MARCKS and MARCKS-like proteins promote cancer stemness and resistance to cancer therapies, demonstrating the potential for MARCKS-targeted therapy as a novel therapeutic strategy to inhibit cancer metastasis and overcome resistance to cancer treatment.

Author Contributions

Writing—original draft preparation, C.-L.C., H.Z., C.-H.C., R.W. and J.D.B.; writing—review and editing, C.-L.C., H.Z., C.-H.C., R.W. and J.D.B. All authors have read and agreed to the published version of the manuscript.

Funding

C.-L.C. acknowledges the funding from the U.S. Department of Defense Congressionally Directed Medical Research Programs (CDMRP) Kidney Cancer Research Program (KCRP) Postdoctoral and Clinical Fellowship Award (W81XWH2210651 Log# KC210195 to C.-L.C.), National Institutes of Health, National Cancer Insititute R21 Grant (R21CA245595 to J.D.B.), and National, Heart, Lung, and Blood Insititute R43 Grant (R43HL15678 to R.W.).

Acknowledgments

Figure 2 were created with BioRender.com.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Siegel, R.L.; Miller, K.D.; Fuchs, H.E.; Jemal, A. Cancer statistics, 2022. CA Cancer J. Clin. 2022, 72, 7–33. [Google Scholar] [CrossRef] [PubMed]
  2. Deyell, M.; Garris, C.S.; Laughney, A.M. Cancer metastasis as a non-healing wound. Br. J. Cancer 2021, 124, 1491–1502. [Google Scholar] [CrossRef] [PubMed]
  3. Fares, J.; Fares, M.Y.; Khachfe, H.H.; Salhab, H.A.; Fares, Y. Molecular principles of metastasis: A hallmark of cancer revisited. Signal Transduct. Target. Ther. 2020, 5, 28. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  4. Phan, T.G.; Croucher, P.I. The dormant cancer cell life cycle. Nat. Rev. Cancer 2020, 20, 398–411. [Google Scholar] [CrossRef]
  5. Majidpoor, J.; Mortezaee, K. Steps in metastasis: An updated review. Med. Oncol. 2021, 38, 3. [Google Scholar] [CrossRef]
  6. Dorris, E.; O’Neill, A.; Hanrahan, K.; Treacy, A.; Watson, R.W. MARCKS promotes invasion and is associated with biochemical recurrence in prostate cancer. Oncotarget 2017, 8, 72021–72030. [Google Scholar] [CrossRef] [Green Version]
  7. Li, C.; Xia, R.; Xue, H.; Hu, Y.; Sun, M.; Fang, D.; Yang, W.; Xiao, F.; Hou, J. Overexpression of MARCKS indicates a poor prognosis of oral squamous cell carcinoma. Oncol. Lett. 2018, 16, 5498–5504. [Google Scholar] [CrossRef] [Green Version]
  8. Mohapatra, P.; Yadav, V.; Toftdahl, M.; Andersson, T. WNT5A-Induced Activation of the Protein Kinase C Substrate MARCKS Is Required for Melanoma Cell Invasion. Cancers 2020, 12, 346. [Google Scholar] [CrossRef] [Green Version]
  9. Rao, G.; Pierobon, M.; Kim, I.-K.; Hsu, W.-H.; Deng, J.; Moon, Y.-W.; Petricoin, E.F.; Zhang, Y.-W.; Wang, Y.; Giaccone, G. Inhibition of AKT1 signaling promotes invasion and metastasis of non-small cell lung cancer cells with K-RAS or EGFR mutations. Sci. Rep. 2017, 7, 7066. [Google Scholar] [CrossRef] [Green Version]
  10. Sheats, M.K.; Yin, Q.; Fang, S.; Park, J.; Crews, A.L.; Parikh, I.; Dickson, B.; Adler, K.B. MARCKS and Lung Disease. Am. J. Respir. Cell Mol. Biol. 2019, 60, 16–27. [Google Scholar] [CrossRef]
  11. Liang, W.; Gao, R.; Yang, M.; Wang, X.; Cheng, K.; Shi, X.; He, C.; Li, Y.; Wu, Y.; Shi, L.; et al. MARCKSL1 promotes the proliferation, migration and invasion of lung adenocarcinoma cells. Oncol. Lett. 2020, 19, 2272–2280. [Google Scholar] [CrossRef] [Green Version]
  12. Aderem, A. The Marcks brothers: A family of protein kinase C substrates. Cell 1992, 71, 713–716. [Google Scholar] [CrossRef]
  13. Björkblom, B.; Padzik, A.; Mohammad, H.; Westerlund, N.; Komulainen, E.; Hollos, P.; Parviainen, L.; Papageorgiou, A.C.; Iljin, K.; Kallioniemi, O.; et al. c-Jun N-Terminal Kinase Phosphorylation of MARCKSL1 Determines Actin Stability and Migration in Neurons and in Cancer Cells. Mol. Cell. Biol. 2012, 32, 3513–3526. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. Chen, Z.; Zhang, W.; Selmi, C.; Ridgway, W.M.; Leung, P.S.C.; Zhang, F.; Gershwin, M.E. The myristoylated alanine-rich C-kinase substrates (MARCKS): A membrane-anchored mediator of the cell function. Autoimmun. Rev. 2021, 20, 102942. [Google Scholar] [CrossRef] [PubMed]
  15. Fong, L.W.R.; Yang, D.C.; Chen, C.-H. Myristoylated alanine-rich C kinase substrate (MARCKS): A multirole signaling protein in cancers. Cancer Metastasis Rev. 2017, 36, 737–747. [Google Scholar] [CrossRef] [Green Version]
  16. Iyer, D.N.; Faruq, O.; Zhang, L.; Rastgoo, N.; Liu, A.; Chang, H. Pathophysiological roles of myristoylated alanine-rich C-kinase substrate (MARCKS) in hematological malignancies. Biomark. Res. 2021, 9, 34. [Google Scholar] [CrossRef]
  17. Wu, W.C.; Walaas, S.I.; Nairn, A.C.; Greengard, P. Calcium/phospholipid regulates phosphorylation of a Mr “87k” substrate protein in brain synaptosomes. Proc. Natl. Acad. Sci. USA 1982, 79, 5249–5253. [Google Scholar] [CrossRef] [Green Version]
  18. Hartwig, J.H.; Thelen, M.; Resen, A.; Janmey, P.A.; Nairn, A.C.; Aderem, A. MARCKS is an actin filament crosslinking protein regulated by protein kinase C and calcium–calmodulin. Nature 1992, 356, 618–622. [Google Scholar] [CrossRef]
  19. Green, T.D.; Crews, A.L.; Park, J.; Fang, S.; Adler, K.B. Regulation of mucin secretion and inflammation in asthma: A role for MARCKS protein? Biochim. Biophys. Acta 2011, 1810, 1110–1113. [Google Scholar] [CrossRef] [Green Version]
  20. Vergères, G.; Manenti, S.; Weber, T.; Stürzinger, C. The Myristoyl Moiety of Myristoylated Alanine-rich C Kinase Substrate (MARCKS) and MARCKS-related Protein Is Embedded in the Membrane. J. Biol. Chem. 1995, 270, 19879–19887. [Google Scholar] [CrossRef]
  21. Czech, M.P. PIP2 and PIP3: Complex Roles at the Cell Surface. Cell 2000, 100, 603–606. [Google Scholar] [CrossRef] [Green Version]
  22. Tanabe, A.; Kamisuki, Y.; Hidaka, H.; Suzuki, M.; Negishi, M.; Takuwa, Y. PKC phosphorylates MARCKS Ser159 not only directly but also through RhoA/ROCK. Biochem. Biophys. Res. Commun. 2006, 345, 156–161. [Google Scholar] [CrossRef] [PubMed]
  23. Kalwa, H.; Michel, T. The MARCKS Protein Plays a Critical Role in Phosphatidylinositol 4,5-Bisphosphate Metabolism and Directed Cell Movement in Vascular Endothelial Cells. J. Biol. Chem. 2011, 286, 2320–2330. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  24. Laux, T.; Fukami, K.; Thelen, M.; Golub, T.; Frey, D.; Caroni, P. Gap43, Marcks, and Cap23 Modulate Pi(4,5)p2 at Plasmalemmal Rafts, and Regulate Cell Cortex Actin Dynamics through a Common Mechanism. J. Cell Biol. 2000, 149, 1455–1472. [Google Scholar] [CrossRef] [Green Version]
  25. Chen, X.; Rotenberg, S.A. PhosphoMARCKS drives motility of mouse melanoma cells. Cell. Signal. 2010, 22, 1097–1103. [Google Scholar] [CrossRef] [Green Version]
  26. Li, Y.; Martin, L.D.; Spizz, G.; Adler, K.B. MARCKS Protein Is a Key Molecule Regulating Mucin Secretion by Human Airway Epithelial Cells in Vitro. J. Biol. Chem. 2001, 276, 40982–40990. [Google Scholar] [CrossRef] [Green Version]
  27. Sheats, M.K.; Sung, E.J.; Adler, K.B.; Jones, S.L. In Vitro Neutrophil Migration Requires Protein Kinase C-Delta (δ-PKC)-Mediated Myristoylated Alanine-Rich C-Kinase Substrate (MARCKS) Phosphorylation. Inflammation 2015, 38, 1126–1141. [Google Scholar] [CrossRef] [Green Version]
  28. Eckert, R.E.; Neuder, L.E.; Park, J.; Adler, K.B.; Jones, S.L. Myristoylated Alanine-Rich C-Kinase Substrate (MARCKS) Protein Regulation of Human Neutrophil Migration. Am. J. Respir. Cell Mol. Biol. 2010, 42, 586–594. [Google Scholar] [CrossRef] [Green Version]
  29. Green, T.D.; Park, J.; Yin, Q.; Fang, S.; Crews, A.L.; Jones, S.L.; Adler, K.B. Directed migration of mouse macrophages in vitro involves myristoylated alanine-rich C-kinase substrate (MARCKS) protein. J. Leukoc. Biol. 2012, 92, 633–639. [Google Scholar] [CrossRef] [Green Version]
  30. Ott, L.E.; Sung, E.J.; Melvin, A.T.; Sheats, M.K.; Haugh, J.M.; Adler, K.B.; Jones, S.L. Fibroblast Migration Is Regulated by Myristoylated Alanine-Rich C-Kinase Substrate (MARCKS) Protein. PLoS ONE 2013, 8, e66512. [Google Scholar] [CrossRef]
  31. Rombouts, K.; Mello, T.; Liotta, F.; Galli, A.; Caligiuri, A.; Annunziato, F.; Pinzani, M. MARCKS actin-binding capacity mediates actin filament assembly during mitosis in human hepatic stellate cells. Am. J. Physiol. Cell Physiol. 2012, 303, C357–C367. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  32. Schulman, H. Chapter 4—Intracellular Signaling. In From Molecules to Networks, 3rd ed.; Byrne, J.H., Heidelberger, R., Waxham, M.N., Eds.; Academic Press: Boston, MA, USA, 2014; pp. 119–148. [Google Scholar]
  33. Toker, A. Phosphatidylinositol Bisphosphate and Trisphosphate. In Encyclopedia of Biological Chemistry, 2nd ed.; Lennarz, W.J., Lane, M.D., Eds.; Academic Press: Waltham, MA, USA, 2013; pp. 451–455. [Google Scholar]
  34. Mandal, K. Review of PIP2 in Cellular Signaling, Functions and Diseases. Int. J. Mol. Sci. 2020, 21, 8342. [Google Scholar] [CrossRef] [PubMed]
  35. Damera, G.; Jester, W.F.; Jiang, M.; Zhao, H.; Fogle, H.W.; Mittelman, M.; Haczku, A.; Murphy, E.; Parikh, I.; Panettieri, R.A. Inhibition of myristoylated alanine-rich C kinase substrate (MARCKS) protein inhibits ozone-induced airway neutrophilia and inflammation. Exp. Lung Res. 2010, 36, 75–84. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  36. Takashi, S.; Park, J.; Fang, S.; Koyama, S.; Parikh, I.; Adler, K.B. A Peptide Against the N-Terminus of Myristoylated Alanine-Rich C Kinase Substrate Inhibits Degranulation of Human Leukocytes In Vitro. Am. J. Respir. Cell Mol. Biol. 2006, 34, 647–652. [Google Scholar] [CrossRef] [Green Version]
  37. Li, J.; D’Annibale-Tolhurst, M.A.; Adler, K.B.; Fang, S.; Yin, Q.; Birkenheuer, A.J.; Levy, M.G.; Jones, S.L.; Sung, E.J.; Hawkins, E.C.; et al. A Myristoylated Alanine-Rich C Kinase Substrate–Related Peptide Suppresses Cytokine mRNA and Protein Expression in LPS-Activated Canine Neutrophils. Am. J. Respir. Cell Mol. Biol. 2013, 48, 314–321. [Google Scholar] [CrossRef] [Green Version]
  38. Button, E.; Shapland, C.; Lawson, D. Actin, its associated proteins and metastasis. Cell Motil. Cytoskelet. 1995, 30, 247–251. [Google Scholar] [CrossRef]
  39. Reed, J.C.; Rapp, U.; Cuddy, M.P. Transformed 3T3 cells have reduced levels and altered subcellular distribution of the major PKC substrate protein marcks. Cell. Signal. 1991, 3, 569–576. [Google Scholar] [CrossRef]
  40. Hanada, S.; Kakehashi, A.; Nishiyama, N.; Wei, M.; Yamano, S.; Chung, K.; Komatsu, H.; Inoue, H.; Suehiro, S.; Wanibuchi, H. Myristoylated alanine-rich C-kinase substrate as a prognostic biomarker in human primary lung squamous cell carcinoma. Cancer Biomark. 2013, 13, 289–298. [Google Scholar] [CrossRef]
  41. Chen, C.-H.; Chiu, C.-L.; Adler, K.B.; Wu, R. A Novel Predictor of Cancer Malignancy: Up-regulation of Myristoylated Alanine-Rich C Kinase Substrate Phosphorylation in Lung Cancer. Am. J. Respir. Crit. Care Med. 2014, 189, 1002–1004. [Google Scholar] [CrossRef] [Green Version]
  42. Chen, C.-H.; Thai, P.; Yoneda, K.; Adler, K.B.; Yang, P.-C.; Wu, R. A peptide that inhibits function of Myristoylated Alanine-Rich C Kinase Substrate (MARCKS) reduces lung cancer metastasis. Oncogene 2014, 33, 3696–3706. [Google Scholar] [CrossRef]
  43. Rohrbach, T.D.; Jarboe, J.S.; Anderson, J.C.; Trummell, H.Q.; Hicks, P.H.; Weaver, A.N.; Yang, E.S.; Oster, R.A.; Deshane, J.S.; Steele, C.; et al. Targeting the effector domain of the myristoylated alanine rich C-kinase substrate enhances lung cancer radiation sensitivity. Int. J. Oncol. 2014, 46, 1079–1088. [Google Scholar] [CrossRef] [Green Version]
  44. Liu, J.; Chen, S.-J.; Hsu, S.-W.; Zhang, J.; Li, J.-M.; Yang, D.C.; Gu, S.; Pinkerton, K.E.; Chen, C.-H. MARCKS cooperates with NKAP to activate NF-kB signaling in smoke-related lung cancer. Theranostics 2021, 11, 4122–4136. [Google Scholar] [CrossRef] [PubMed]
  45. Adler, K.B.; Dickson, B. An Inhaled MARCKS (Myristoylated Alanine-Rich C Kinase Substrate)—Inhibitory Drug, BIO-11006, Elicited a StatisticallySignificant Result (p = 0.02) in Overall Response Rate (ORR) After 3 Months Compared to Standard of Care Chemotherapy in a Phase 2 Trial of Late Stage Non Small Cell Lung Cancer (NSCLC). Am. J. Resp. Crit. Care 2020, 201, A6197. [Google Scholar]
  46. Browne, B.C.; Hochgräfe, F.; Wu, J.; Millar, E.K.A.; Barraclough, J.; Stone, A.; McCloy, R.A.; Lee, C.S.; Roberts, C.; Ali, N.A.; et al. Global characterization of signalling networks associated with tamoxifen resistance in breast cancer. FEBS J. 2013, 280, 5237–5257. [Google Scholar] [CrossRef]
  47. Manai, M.; Thomassin-Piana, J.; Gamoudi, A.; Finetti, P.; Lopez, M.; Eghozzi, R.; Ayadi, S.; Lamine, O.B.; Manai, M.; Rahal, K.; et al. MARCKS protein overexpression in inflammatory breast cancer. Oncotarget 2017, 8, 6246–6257. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  48. Manai, M.; Abdeljaoued, S.; Goucha, A.; Adouni, O.; Bettaieb, I.; Bouzaien, H.; Rahal, K.; Birnbaum, D.; Bertucci, F.; Gamoudi, A. MARCKS protein overexpression is associated with poor prognosis in male breast cancer. Cancer Biomark. 2019, 26, 513–522. [Google Scholar] [CrossRef]
  49. Chen, C.-H.; Cheng, C.-T.; Yuan, Y.; Zhai, J.; Arif, M.; Fong, L.W.R.; Wu, R.; Ann, D.K. Elevated MARCKS phosphorylation contributes to unresponsiveness of breast cancer to paclitaxel treatment. Oncotarget 2015, 6, 15194–15208. [Google Scholar] [CrossRef] [Green Version]
  50. Cho, S.J.; La, M.-H.; Ahn, J.K.; Meadows, G.G.; Joe, C.O. Tob-Mediated Cross-Talk between MARCKS Phosphorylation and ErbB-2 Activation. Biochem. Biophys. Res. Commun. 2001, 283, 273–277. [Google Scholar] [CrossRef]
  51. Yu, D.; Hung, M.-C. Overexpression of ErbB2 in cancer and ErbB2-targeting strategies. Oncogene 2000, 19, 6115–6121. [Google Scholar] [CrossRef] [Green Version]
  52. Chen, C.-H.; Fong, L.W.R.; Yu, E.; Wu, R.; Trott, J.F.; Weiss, R.H. Upregulation of MARCKS in kidney cancer and its potential as a therapeutic target. Oncogene 2017, 36, 3588–3598. [Google Scholar] [CrossRef] [Green Version]
  53. Techasen, A.; Loilome, W.; Namwat, N.; Takahashi, E.; Sugihara, E.; Puapairoj, A.; Miwa, M.; Saya, H.; Yongvanit, P. Myristoylated alanine-rich C kinase substrate phosphorylation promotes cholangiocarcinoma cell migration and metastasis via the protein kinase C-dependent pathway. Cancer Sci. 2010, 101, 658–665. [Google Scholar] [CrossRef] [PubMed]
  54. Song, J.; Wang, Q.; Luo, Y.; Yuan, P.; Tang, C.; Hui, Y.; Wang, Z. miR-34c-3p inhibits cell proliferation, migration and invasion of hepatocellular carcinoma by targeting MARCKS. Int. J. Clin. Exp. Pathol. 2015, 8, 12728–12737. [Google Scholar]
  55. Rombouts, K.; Carloni, V.; Mello, T.; Omenetti, S.; Galastri, S.; Madiai, S.; Galli, A.; Pinzani, M. Myristoylated Alanine-Rich protein Kinase C Substrate (MARCKS) expression modulates the metastatic phenotype in human and murine colon carcinoma in vitro and in vivo. Cancer Lett. 2013, 333, 244–252. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Bickeböller, M.; Tagscherer, K.E.; Kloor, M.; Jansen, L.; Chang-Claude, J.; Brenner, H.; Hoffmeister, M.; Toth, C.; Schirmacher, P.; Roth, W.; et al. Functional characterization of the tumor-suppressor MARCKS in colorectal cancer and its association with survival. Oncogene 2015, 34, 1150–1159. [Google Scholar] [CrossRef]
  57. Micallef, J.; Taccone, M.; Mukherjee, J.; Croul, S.; Busby, J.; Moran, M.F.; Guha, A. Epidermal Growth Factor Receptor Variant III–Induced Glioma Invasion Is Mediated through Myristoylated Alanine-Rich Protein Kinase C Substrate Overexpression. Cancer Res. 2009, 69, 7548–7556. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  58. Jarboe, J.S.; Anderson, J.C.; Duarte, C.W.; Mehta, T.; Nowsheen, S.; Hicks, P.H.; Whitley, A.C.; Rohrbach, T.D.; McCubrey, R.O.; Chiu, S.; et al. MARCKS Regulates Growth and Radiation Sensitivity and Is a Novel Prognostic Factor for Glioma. Clin. Cancer Res. 2012, 18, 3030–3041. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  59. Li, T.; Li, D.; Sha, J.; Sun, P.; Huang, Y. MicroRNA-21 directly targets MARCKS and promotes apoptosis resistance and invasion in prostate cancer cells. Biochem. Biophys. Res. Commun. 2009, 383, 280–285. [Google Scholar] [CrossRef]
  60. Finlayson, A.E.; Freeman, K.W. A Cell Motility Screen Reveals Role for MARCKS-Related Protein in Adherens Junction Formation and Tumorigenesis. PLoS ONE 2009, 4, e7833. [Google Scholar] [CrossRef] [Green Version]
  61. Tomiyama, E.; Matsuzaki, K.; Fujita, K.; Shiromizu, T.; Narumi, R.; Jingushi, K.; Koh, Y.; Matsushita, M.; Nakano, K.; Hayashi, Y.; et al. Proteomic analysis of urinary and tissue-exudative extracellular vesicles to discover novel bladder cancer biomarkers. Cancer Sci. 2021, 112, 2033–2045. [Google Scholar] [CrossRef]
  62. Yokoyama, Y.; Ito, T.; Hanson, V.; Schwartz, G.K.; Aderem, A.A.; Holland, J.F.; Tamaya, T.; Ohnuma, T. PMA-induced reduction in invasiveness is associated with hyperphosphorylation of MARCKS and talin in invasive bladder cancer cells. Int. J. Cancer 1998, 75, 774–779. [Google Scholar] [CrossRef]
  63. Chen, C.-H.; Statt, S.; Chiu, C.-L.; Thai, P.; Arif, M.; Adler, K.B.; Wu, R. Targeting Myristoylated Alanine-Rich C Kinase Substrate Phosphorylation Site Domain in Lung Cancer. Mechanisms and Therapeutic Implications. Am. J. Respir. Crit. Care Med. 2014, 190, 1127–1138. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  64. Garg, R.; Benedetti, L.G.; Abera, M.B.; Wang, H.; Abba, M.; Kazanietz, M.G. Protein kinase C and cancer: What we know and what we do not. Oncogene 2014, 33, 5225–5237. [Google Scholar] [CrossRef] [PubMed]
  65. Sadeghi, M.M.; Salama, M.F.; Hannun, Y.A. Protein Kinase C as a Therapeutic Target in Non-Small Cell Lung Cancer. Int. J. Mol. Sci. 2021, 22, 5527. [Google Scholar] [CrossRef] [PubMed]
  66. Regala, R.P.; Davis, R.K.; Kunz, A.; Khoor, A.; Leitges, M.; Fields, A.P. Atypical Protein Kinase Cι Is Required for Bronchioalveolar Stem Cell Expansion and Lung Tumorigenesis. Cancer Res. 2009, 69, 7603–7611. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  67. Ali, S.A.; Justilien, V.; Jamieson, L.; Murray, N.R.; Fields, A.P. Protein Kinase Cι Drives a NOTCH3-dependent Stem-like Phenotype in Mutant KRAS Lung Adenocarcinoma. Cancer Cell 2016, 29, 367–378. [Google Scholar] [CrossRef] [Green Version]
  68. Tam, W.L.; Lu, H.; Buikhuisen, J.; Soh, B.S.; Lim, E.; Reinhardt, F.; Wu, Z.J.; Krall, J.A.; Bierie, B.; Guo, W.; et al. Protein Kinase C α Is a Central Signaling Node and Therapeutic Target for Breast Cancer Stem Cells. Cancer Cell 2013, 24, 347–364. [Google Scholar] [CrossRef] [Green Version]
  69. Affer, M.; Dao, S.; Liu, C.; Olshen, A.B.; Mo, Q.; Viale, A.; Lambek, C.L.; Marr, T.G.; Clarkson, B.D. Gene Expression Differences between Enriched Normal and Chronic Myelogenous Leukemia Quiescent Stem/Progenitor Cells and Correlations with Biological Abnormalities. J. Oncol. 2011, 2011, 798592. [Google Scholar] [CrossRef]
  70. Brandi, J.; Pozza, E.D.; Dando, I.; Biondani, G.; Robotti, E.; Jenkins, R.; Elliott, V.; Park, K.; Marengo, E.; Costello, E.; et al. Secretome protein signature of human pancreatic cancer stem-like cells. J. Proteom. 2016, 136, 1–12. [Google Scholar] [CrossRef] [Green Version]
  71. Chen, Z.; Liu, Y.; Yao, L.; Guo, S.; Gao, Y.; Zhu, P. The long noncoding RNA lncZic2 drives the self-renewal of liver tumor–initiating cells via the protein kinase C substrates MARCKS and MARCKSL1. J. Biol. Chem. 2018, 293, 7982–7992. [Google Scholar] [CrossRef] [Green Version]
  72. Chatterjee, N.; Bivona, T.G. Polytherapy and Targeted Cancer Drug Resistance. Trends Cancer 2019, 5, 170–182. [Google Scholar] [CrossRef]
  73. Dianat-Moghadam, H.; Heidarifard, M.; Jahanban-Esfahlan, R.; Panahi, Y.; Hamishehkar, H.; Pouremamali, F.; Rahbarghazi, R.; Nouri, M. Cancer stem cells-emanated therapy resistance: Implications for liposomal drug delivery systems. J. Control. Release 2018, 288, 62–83. [Google Scholar] [CrossRef] [PubMed]
  74. Huang, T.; Song, X.; Xu, D.; Tiek, D.; Goenka, A.; Wu, B.; Sastry, N.; Hu, B.; Cheng, S.-Y. Stem cell programs in cancer initiation, progression, and therapy resistance. Theranostics 2020, 10, 8721–8743. [Google Scholar] [CrossRef] [PubMed]
  75. Pattabiraman, D.R.; Weinberg, R.A. Tackling the cancer stem cells—What challenges do they pose? Nat. Rev. Drug Discov. 2014, 13, 497–512. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Kim, Y.E.; Kim, E.-K.; Song, M.-J.; Kim, T.-Y.; Jang, H.H.; Kang, D. SILAC-Based Quantitative Proteomic Analysis of Oxaliplatin-Resistant Pancreatic Cancer Cells. Cancers 2021, 13, 724. [Google Scholar] [CrossRef]
  77. Wenzel, T.; Büch, T.; Urban, N.; Weirauch, U.; Schierle, K.; Aigner, A.; Schaefer, M.; Kalwa, H. Restoration of MARCK enhances chemosensitivity in cancer. J. Cancer Res. Clin. Oncol. 2020, 146, 843–858. [Google Scholar] [CrossRef] [Green Version]
  78. Robey, R.W.; Pluchino, K.M.; Hall, M.D.; Fojo, A.T.; Bates, S.E.; Gottesman, M.M. Revisiting the role of ABC transporters in multidrug-resistant cancer. Nat. Rev. Cancer 2018, 18, 452–464. [Google Scholar] [CrossRef]
  79. Xiao, H.; Zheng, Y.; Ma, L.; Tian, L.; Sun, Q. Clinically-Relevant ABC Transporter for Anti-Cancer Drug Resistance. Front. Pharmacol. 2021, 12, 648407. [Google Scholar] [CrossRef]
  80. Eustace, N.J.; Anderson, J.C.; Langford, C.P.; Trummell, H.Q.; Hicks, P.H.; Jarboe, J.S.; Mobley, J.A.; Hjelmeland, A.B.; Hackney, J.R.; Pedersen, R.T.; et al. Myristoylated alanine-rich C-kinase substrate effector domain phosphorylation regulates the growth and radiation sensitization of glioblastoma. Int. J. Oncol. 2019, 54, 2039–2053. [Google Scholar] [CrossRef] [Green Version]
  81. Agrawal, A.; Murphy, E.C., III; Park, J.; Adler, K.B.; Parikh, I. Aerosolized BIO-11006, a Novel MARCKS- Related Peptide, Improves Airway Obstruction in a Mouse Model of Mucus Hypersecretion. J. Epithel. Biol. Pharmacol. 2011, 4, 1–6. [Google Scholar] [CrossRef]
  82. Zhang, L.; Rastgoo, N.; Wu, J.; Zhang, M.; Pourabdollah, M.; Zacksenhaus, E.; Chen, Y.; Chang, H. MARCKS inhibition cooperates with autophagy antagonists to potentiate the effect of standard therapy against drug-resistant multiple myeloma. Cancer Lett. 2020, 480, 29–38. [Google Scholar] [CrossRef]
  83. Eustace, N.J.; Anderson, J.C.; Warram, J.M.; Widden, H.N.; Pedersen, R.T.; Alrefai, H.; Patel, Z.; Hicks, P.H.; Placzek, W.J.; Gillespie, G.Y.; et al. A cell-penetrating MARCKS mimetic selectively triggers cytolytic death in glioblastoma. Oncogene 2020, 39, 6961–6974. [Google Scholar] [CrossRef] [PubMed]
  84. Corradin, S.; Ransijn, A.; Corradin, G.; Bouvier, J.; Delgado, M.B.; Fernández-Carneado, J.; Mottram, J.C.; Vergères, G.; Mauël, J. Novel peptide inhibitors of Leishmania gp63 based on the cleavage site of MARCKS (myristoylated alanine-rich C kinase substrate)-related protein. Biochem. J. 2002, 367, 761–769. [Google Scholar] [CrossRef] [PubMed]
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Figure 1. The publication trend of MARCKS research related to solid tumors in PubMed from 1989 to 2021. The black dots represent the publication ratio (%) of each year in which the publications of MARCKS research related to solid tumors were divided by the total publications of MARCKS research. The red line demonstrates the trend of the non-linear regression fit curve analyzed from each year’s publication ratio by GraphPad Prism (v6.07).
Figure 1. The publication trend of MARCKS research related to solid tumors in PubMed from 1989 to 2021. The black dots represent the publication ratio (%) of each year in which the publications of MARCKS research related to solid tumors were divided by the total publications of MARCKS research. The red line demonstrates the trend of the non-linear regression fit curve analyzed from each year’s publication ratio by GraphPad Prism (v6.07).
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Cancers 14 04925 g002 550
Figure 2. MARCKS participates in mediating target signaling pathways to drive malignant phenotypes that lead to cancer metastasis (through actin rearrangement, MMP9, ErbB2, NF-κB, and AKT pathways), cancer stemness (through the NF-κB pathway), and therapeutic resistance (through AKT, ABCB1, and stemness genes—SOX2, OCT4, and CD133).
Figure 2. MARCKS participates in mediating target signaling pathways to drive malignant phenotypes that lead to cancer metastasis (through actin rearrangement, MMP9, ErbB2, NF-κB, and AKT pathways), cancer stemness (through the NF-κB pathway), and therapeutic resistance (through AKT, ABCB1, and stemness genes—SOX2, OCT4, and CD133).
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Table
Table 1. The roles of MARCKS and MARCKSL1 in different solid cancers.
Table 1. The roles of MARCKS and MARCKSL1 in different solid cancers.
Cancer Type [Reference]RoleModelsProliferation
/Apoptosis		Migration
/Invasion		Tumor
Growth		MetastasisSurvival/Grade/StageTreatment ResistanceTarget
NSCLC [42]Procell line, xenograft, and TMA ↑ ↑higher grade E-cad, pAKT, pPI3K, and Slug
NSCLC [41]ProTMA ↑higher stage
NSCLC [63]Procell line, xenograft, and TMAproliferation ↑
/apoptosis ↓		 ↑↑shorter survivalerlotinibpAKT
NSCLC [45]Proclinical trialBIO-11006 (MARCK inhibitor) plus carboplatin showed a less disease progression and a higher response rate compared to carboplatin alone.
LC [43]Procell line, TMA, and TCGAproliferation ↑
/apoptosis ↓		 shorter survivalradiation
LC [44]Procell line, xenograft, and TMAproliferation ↑↑ shorter survival NF-κB, EMT, and stemness
LSCC [40]ProTMA shorter survival
BC [46]Procell line and TMAproliferation ↑↑ shorter survivaltamoxifen
BC [47,48]ProTMA shorter survival
BC [49]Procell line, xenograft, and TMAproliferation ↑
/apoptosis ↑		↑↑↑shorter survivalpaclitaxelangiogenic factors
BC [50]Procell linesproliferation ↑ ErbB2
RCC [52]Procell line, xenograft, and TMAproliferation ↑↑↑ higher graderegorafenibAKT, mTOR, VEGF, and MM9
CCA [53]Procell line, xenograft, and human tissue ↑ ↑shorter survival
HCC [54]Procell line ↑
CC [55]Procell line and xenograft ↑ ↑ AURKB
CC [56]Supcell line and TMAapoptosis ↑ longer survival TRAIL and AKT
GBM [58]Supcell line, xenograft, clinical trial, and TCGAproliferation ↓ ↓ longer survival
PCa [6]Procell line and TMA ↑ more recurrence
PCa [59]Supcell line ↓
BC, PCa [60] *Supcell line and xenograft ↓↓ E-cad,
b-catenin, and APC
PCa [13] *Supcell line ↓
BlaC [62]Supcell line ↓
Abbreviations: NSCLC, non-small cell lung cancer; LSCC, lung squamous cell carcinoma; LC, lung cancer; BC, breast cancer; RCC, renal cell carcinoma; CCA, cholangiocarcinoma; HCC, hepatocellular carcinoma; CC, colon cancer; GBM, glioblastoma multiforme; PCa, prostate cancer; BlaC, bladder cancer; Pro, promotion; Sup, suppression; * studies on MARCKSL1. ↑, increase; ↓, decrease.
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Chiu, C.-L.; Zhao, H.; Chen, C.-H.; Wu, R.; Brooks, J.D. The Role of MARCKS in Metastasis and Treatment Resistance of Solid Tumors. Cancers 2022, 14, 4925. https://doi.org/10.3390/cancers14194925

AMA Style

Chiu C-L, Zhao H, Chen C-H, Wu R, Brooks JD. The Role of MARCKS in Metastasis and Treatment Resistance of Solid Tumors. Cancers. 2022; 14(19):4925. https://doi.org/10.3390/cancers14194925

Chicago/Turabian Style

Chiu, Chun-Lung, Hongjuan Zhao, Ching-Hsien Chen, Reen Wu, and James D. Brooks. 2022. "The Role of MARCKS in Metastasis and Treatment Resistance of Solid Tumors" Cancers 14, no. 19: 4925. https://doi.org/10.3390/cancers14194925

APA Style

Chiu, C. -L., Zhao, H., Chen, C. -H., Wu, R., & Brooks, J. D. (2022). The Role of MARCKS in Metastasis and Treatment Resistance of Solid Tumors. Cancers, 14(19), 4925. https://doi.org/10.3390/cancers14194925

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