A Novel Predictor of Cancer Malignancy: Up-regulation of Myristoylated Alanine-Rich C Kinase Substrate Phosphorylation in Lung Cancer

Chen, Ching-Hsien; Chiu, Chun Lung; Adler, Kenneth B.; Wu, Reen

doi:10.1164/rccm.201401-0053le

Cited by 16 publications

(19 citation statements)

References 16 publications

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“…20 In contrast, following phosphorylation at the PSD, phosphorylated MARCKS promotes the activation of AKT due to releasing PIP2 pools. 28,42 Such a dual contribution of MARCKS may explain why an upregulation of MARCKS would not necessarily contribute to tumorigenesis, 20,32 whereas an increase in MARCKS phosphorylation would. 22,23,26 By reducing MARCKS phosphorylation and trapping PIP2 pools at the membrane, MPS effectively inactivates the PI3K/AKT pathway.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of MARCKS in kidney cancer and its potential as a therapeutic target

Chen

Fong

et al. 2017

Oncogene

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Targeted therapeutics, such as those abrogating hypoxia inducible factor (HIF)/vascular endothelial growth factor signaling, are initially effective against kidney cancer (or renal cell carcinoma, RCC); however, drug resistance frequently occurs via subsequent activation of alternative pathways. Through genome-scale integrated analysis of the HIF-α network, we identified the major protein kinase C substrate MARCKS (myristoylated alanine-rich C kinase substrate) as a potential target molecule for kidney cancer. In a screen of nephrectomy samples from 56 patients with RCC, we found that MARCKS expression and its phosphorylation are increased and positively correlate with tumor grade. Genetic and pharmacologic suppression of MARCKS in high-grade RCC cell lines in vitro led to a decrease in cell proliferation and migration. We further demonstrated that higher MARCKS expression promotes growth and angiogenesis in vivo in an RCC xenograft tumor. MARCKS acted upstream of the AKT/mTOR pathway, activating HIF-target genes, notably vascular endothelial growth factor-A. Following knockdown of MARCKS in RCC cells, the IC50 of the multikinase inhibitor regorafenib was reduced. Surprisingly, attenuation of MARCKS using the MPS peptide synergistically interacted with regorafenib treatment and decreased survival of kidney cancer cells through inactivation of AKT and mTOR. Our data suggest a major contribution of MARCKS to kidney cancer growth and provide an alternative therapeutic strategy of improving the efficacy of multikinase inhibitors.

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Section: Discussionmentioning

confidence: 99%

Upregulation of MARCKS in kidney cancer and its potential as a therapeutic target

Chen

Fong

et al. 2017

Oncogene

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“…We also found peptide sequences from histones (including histones H1.2, H2B, and H4), heat shock protein 70, ribosomal proteins (40S and 60S), and PARP1, as well as Prohibitin-2 and myristoylated alaninerich protein kinase C substrate (MARCK), which have putative roles in invasion and metastasis ( Fig. 1, Table 1) (8,(22)(23)(24). The most striking ATDC-interacting protein identified by this screen was RNF8 (37% peptide coverage by mass spectroscopy, Fig.…”

Section: Atdc Bindsmentioning

confidence: 94%

ATDC (Ataxia Telangiectasia Group D Complementing) Promotes Radioresistance through an Interaction with the RNF8 Ubiquitin Ligase

Yang

Palmbos

Wang

et al. 2015

Journal of Biological Chemistry

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Background: ATDC/TRIM29 promotes resistance to ionizing radiation, but the factor(s) that mediate this effect are incompletely understood. Results: ATDC/TRIM29 binds to RNF8, promoting DNA repair and resistance to IR. Conclusion: Following DNA damage, ATDC/TRIM29 is phosphorylated and interacts with RNF8, promoting DNA repair and cell survival. Significance: The interaction between ATDC/TRIM29 and RNF8 is novel and is important for the DNA damage response.

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“…We previously reported an association between elevated phospho-MARCKS (pSer159/163) and lung cancer malignancy (22,23). To expand on this previous finding, we retrospectively evaluated the relationship between MARCKS activity and overall survival of 195 lung cancer patients by immunohistochemical (IHC) staining.…”

Section: High Phospho-marcks Is Correlated With Poor Survival Of Lungmentioning

confidence: 97%

“…Phosphorylation by protein kinase C (PKC) within MARCKS PSD (Ser159, Ser163, and Ser170) enhances phosphorylated MARCKS (phospho-MARCKS) detachment from membrane and suppresses PIP2 sequestering effect (15,16). In the lung, MARCKS, predominantly phospho-MARCKS, is crucial for controlling mucin secretion and inflammation (17)(18)(19)(20)(21), but only a few studies have revealed its relevance with lung cancer (22,23). Recently, our laboratory discovered that the use of a MANS peptide, targeting MARCKS N-terminal myristoylation site, was able to reduce lung cancer metastasis.…”

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confidence: 99%

Targeting Myristoylated Alanine-Rich C Kinase Substrate Phosphorylation Site Domain in Lung Cancer. Mechanisms and Therapeutic Implications

Chen

Statt

Chiu

et al. 2014

Am J Respir Crit Care Med

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Rationale: Phosphorylation of myristoylated alanine-rich C kinase substrate (phospho-MARCKS) at the phosphorylation site domain (PSD) is crucial for mucus granule secretion and cell motility, but little is known concerning its function in lung cancer.Objectives: We aimed to determine if MARCKS PSD activity can serve as a therapeutic target and to elucidate the molecular basis of this potential. Methods:The clinical relevance of phospho-MARCKS was first confirmed. Next, we used genetic approaches to verify the functionality and molecular mechanism of phospho-MARCKS. Finally, cancer cells were pharmacologically inhibited for MARCKS activity and subjected to functional bioassays. Measurements and Main Results:We demonstrated that higher phospho-MARCKS levels were correlated with shorter overall survival of lung cancer patients. Using shRNA silencing and ectopic expression of wild-type and PSD-mutated (S159/163A) MARCKS, we showed that elevated phospho-MARCKS promoted cancer growth and erlotinib resistance. Further studies demonstrated an interaction of phosphoinositide 3-kinase with MARCKS, but not with phospho-MARCKS. Interestingly, phospho-MARCKS acted in parallel with increased phosphatidylinositol (3,4,5)-triphosphate pools and AKT activation in cells. Through treatment with a 25-mer peptide targeting the MARCKS PSD motif (MPS peptide), we were able to suppress tumor growth and metastasis in vivo, and reduced levels of phospho-MARCKS, phosphatidylinositol (3,4,5)-triphosphate, and AKT activity. This peptide also enhanced the sensitivity of lung cancer cells to erlotinib treatment, especially those with sustained activation of phosphoinositide 3-kinase/AKT signaling.Conclusions: These results suggest a key role for MARCKS PSD in cancer disease and provide a unique strategy for inhibiting the activity of MARCKS PSD as a treatment for lung cancer.

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A Novel Predictor of Cancer Malignancy: Up-regulation of Myristoylated Alanine-Rich C Kinase Substrate Phosphorylation in Lung Cancer

Cited by 16 publications

References 16 publications

Upregulation of MARCKS in kidney cancer and its potential as a therapeutic target

Upregulation of MARCKS in kidney cancer and its potential as a therapeutic target

ATDC (Ataxia Telangiectasia Group D Complementing) Promotes Radioresistance through an Interaction with the RNF8 Ubiquitin Ligase

Targeting Myristoylated Alanine-Rich C Kinase Substrate Phosphorylation Site Domain in Lung Cancer. Mechanisms and Therapeutic Implications

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