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.