MARCKS Regulates Growth and Radiation Sensitivity and Is a Novel Prognostic Factor for Glioma

Abstract

Purpose This study assessed whether Myristoylated Alanine Rich C-Kinase Substrate (MARCKS) can regulate glioblastoma (GBM) growth, radiation sensitivity and clinical outcome. Experimental Design MARCKS protein levels were analyzed in five GBM explant cell lines and eight patient-derived xenograft tumors by immunoblot, and these levels were correlated to proliferation rates and intracranial growth rates, respectively. Manipulation of MARCKS protein levels was assessed by lentiviral-mediated shRNA knockdown in the U251 cell line and MARCKS over-expression in the U87 cell line. The effect of manipulation of MARCKS on proliferation, radiation sensitivity and senescence was assessed. MARCKS gene expression was correlated with survival outcomes in the Repository of Molecular Brain Neoplasia Data (REMBRANDT) Database and The Cancer Genome Atlas (TCGA). Results MARCKS protein expression was inversely correlated with GBM proliferation and intracranial xenograft growth rates. Genetic silencing of MARCKS promoted GBM proliferation and radiation resistance, while MARCKS overexpression greatly reduced GBM growth potential and induced senescence. We found MARCKS gene expression to be directly correlated with survival in both the REMBRANDT and TCGA databases. Specifically, patients with high MARCKS expressing tumors of the Proneural molecular subtype had significantly increased survival rates. This effect was most pronounced in tumors with unmethylated O6-methylguanine DNA methyltransferase (MGMT) promoters, a traditionally poor prognostic factor. Conclusions MARCKS levels impact GBM growth and radiation sensitivity. High MARCKS expressing GBM tumors are associated with improved survival, particularly with unmethylated MGMT promoters. These findings suggest the use of MARCKS as a novel target and biomarker for prognosis in the Proneural subtype of GBM.

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

“…A study on the role of MARCKS as a tumor suppressor in glioma is consistent with this proposition. 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.…”

“…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.…”

“…18–31 MARCKS has also been implicated in lung, breast and pancreatic cancer progression. 22,23,26–31 Intriguingly, MARCKS has been reported to be prometastatic, 18,19,24 but also a tumor suppressor 20,21,32 in glioma, melanoma and colon cancer. Despite these findings in various neoplastic diseases, there has been no information regarding the role of MARCKS in kidney cancer.…”

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

“…Inhibition of MARCKS activity not only reduces airway mucus hypersecretion both in vitro and in vivo (3,5), but also represses inflammatory leukocyte migration and degranulation (6, 7). There have been limited studies on MARCKS in cancer metastasis, but the results have been conflicting (8)(9)(10)(11)(12)(13). This is because MARCKS expression is ubiquitous in various normal and tumor tissues.…”

Myristoylated Alanine-Rich protein Kinase C Substrate (MARCKS) expression modulates the metastatic phenotype in human and murine colon carcinoma in vitro and in vivo

“…Several of these actin-binding proteins are up-or down-regulated in metastatic cell lines and tumours. In particular , recent studies have identified Myristoylat ed Alanine-Ric h C Kinase Substrate (MARCKS) to be implicate d in the pathogenesis of various malignancies such as pituitary and thyroid cancer [3], breast cancer [4], melanoma [5], glioblastoma multiform e cancer [6,7], and cholangiocarci noma [8].…”