Elevated MARCKS phosphorylation contributes to unresponsiveness of breast cancer to paclitaxel treatment

Abstract

Accumulating evidence has suggested that myristoylated alanine-rich C-kinase substrate (MARCKS) is critical for regulating multiple pathophysiological processes. However, the molecular mechanism underlying increased phosphorylation of MARCKS at Ser159/163 (phospho-MARCKS) and its functional consequence in neoplastic disease remain to be established. Herein, we investigated how phospho-MARCKS is regulated in breast carcinoma, and its role in the context of chemotherapy. In a screen of patients with breast tumors, we find that the abundance of phospho-MARCKS, not MARCKS protein per se, increased in breast cancers and positively correlated with tumor grade and metastatic status. Among chemotherapeutic agents, mitotic inhibitors, including paclitaxel, vincristine or eribulin, notably promoted phospho-MARCKS accumulation in multiple breast cancer cells. We further show that phospho-MARCKS acted upstream of Src activation upon paclitaxel exposure. Reduction of phospho-MARCKS by knockdown of MARCKS or pharmacological agents increased paclitaxel sensitivity. Particularly, a known phospho-MARCKS inhibitor, MANS peptide, was demonstrated to increase paclitaxel efficacy and attenuate angiogenesis/metastasis of xenografted breast cancer cells by decreasing abundance of phospho-MARCKS and messages of inflammatory mediators. Our data suggest that unresponsiveness of breast cancer to paclitaxel treatment is, at least in part, mediated by phospho-MARCKS and also provide an alternative therapeutic strategy against breast cancer by improving taxanes sensitivity.

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

“…18,19,22–24,27 Recent studies have indicated that an important function of MARCKS is to provide PI3K with PIP2 pools and thereby activate AKT. 23,27,42 Although the contribution of MARCKS has already been characterized in a handful of solid tumors, most notably carcinomas of the lung, 23,27–29 a role has yet to be demonstrated in kidney cancer.…”

“…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. 23,42 Although treatment with MPS peptide provides a proof-of-concept that targeting MARCKS controls RCC cell growth and regorafenib efficacy, the off-target effects of this peptide in kidney cancer in vivo is an important line of investigation for future studies.…”

“…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.…”

miR-34c-3p acts as a tumor suppressor gene in osteosarcoma by targeting MARCKS

“…It was additionally involved in 12-O-tetradecanoylphorbol-13-acetate-mediated migration of neuroblastoma cells (18). It has previously been suggested that elevated MARCKS phosphorylation contributes to the unresponsiveness of breast cancer to paclitaxel treatment (19). The present study hypothesized that MARCKS was the precise intracellular target of miR-34c-3p by using the miRanda, TargetScan and Pictar databases.…”

MARCKS contributes to stromal cancer-associated fibroblast activation and facilitates ovarian cancer metastasis

“…MARCKS, originally identified as a major target of protein kinase C (PKC), is a key regulatory molecule regulating actin dynamics [27]. Recently, it has been shown to play a fundamental role in mediating chemoresistance of breast and lung cancer [28, 29]. There are limited studies examining MARCKS in EOC metastasis.…”