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

Ching-Hsien Chen, Chun Ting Cheng, Yuan Yuan, Jing Zhai, Muhammad Arif, Lon Wolf R Fong, Reen Wu, David K. Ann

Research output: Contribution to journalArticle

21 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)15194-15208
Number of pages15
JournalOncotarget
Volume6
Issue number17
StatePublished - 2015

Keywords

  • Breast cancer
  • MANS peptide
  • Mitotic inhibitor
  • Paclitaxel
  • Phospho-MARCKS

ASJC Scopus subject areas

  • Oncology

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    Chen, C-H., Cheng, C. T., Yuan, Y., Zhai, J., Arif, M., Fong, L. W. R., Wu, R., & Ann, D. K. (2015). Elevated MARCKS phosphorylation contributes to unresponsiveness of breast cancer to paclitaxel treatment. Oncotarget, 6(17), 15194-15208.