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.
Highlights
Cytotoxic chemotherapy remains a mainstay for breast cancer treatment, especially for recurrent or metastatic breast cancer (MBC) [1]
To investigate the role of phospho-myristoylated alanine-rich C-kinase substrate (MARCKS) (Ser159/163) in breast cancer, we evaluated phosphoMARCKS abundance by IHC analysis in primary tumor tissue sections from 21 patients with breast carcinomas
Phospho-MARCKS signals were significantly lower in noninvasive tumors compared to those invasive breast carcinomas and lymph node metastatic tumors (Figure 1B, right; p = 0.048)
Summary
Cytotoxic chemotherapy remains a mainstay for breast cancer treatment, especially for recurrent or metastatic breast cancer (MBC) [1]. There are two main modes of action within mitotic inhibitors: 1) taxanes (which include paclitaxel and docetaxel) stabilize microtubules and promote polymerization; 2) vinca alkaloids and the newly approved eribulin destabilize microtubules and prevent growth [2, 3] Among these agents, the taxanes have served as a standard first-line www.impactjournals.com/oncotarget option for triple-negative breast cancer (TNBC) and MBC. A direct comparison of paclitaxel treatment in 585 breast cancer patients, single-agent paclitaxel as a chemotherapeutic regimen for MBC demonstrated lower response rates both in weekly and 3-weekly administrations (40% and 28%) [7] This poor response to chemotherapy has created challenges in clinical practice; and there is an urgent need to identify a predictive marker to identify responders and non-responders
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