title: 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.
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine and Center for Comparative Respiratory Biology and Medicine, University of California Davis, California, USA.
authors.forename: Ching-Hsien
authors.initials: CH
authors.lastname: Chen
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, California, USA.|Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, California, USA.
authors.forename: Chun-Ting
authors.initials: CT
authors.lastname: Cheng
authors.affiliation: Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, California, USA.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yuan
authors.affiliation: Department of Pathology, City of Hope Comprehensive Cancer Center, Duarte, California, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhai
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine and Center for Comparative Respiratory Biology and Medicine, University of California Davis, California, USA.
authors.forename: Muhammad
authors.initials: M
authors.lastname: Arif
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine and Center for Comparative Respiratory Biology and Medicine, University of California Davis, California, USA.
authors.forename: Lon Wolf R
authors.initials: LW
authors.lastname: Fong
authors.affiliation: Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine and Center for Comparative Respiratory Biology and Medicine, University of California Davis, California, USA.
authors.forename: Reen
authors.initials: R
authors.lastname: Wu
authors.affiliation: Department of Molecular Pharmacology, Beckman Research Institute, City of Hope, Duarte, California, USA.|Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute, City of Hope, Duarte, California, USA.
authors.forename: David K
authors.initials: DK
authors.lastname: Ann
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D061986:MCF-7 Cells; D008565:Membrane Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D017239:Paclitaxel / Q000627:therapeutic use*; D010446:Peptide Fragments / Q000494:pharmacology; D010766:Phosphorylation; D034622:RNA Interference; D034741:RNA, Small Interfering; D050257:Tubulin Modulators / Q000627:therapeutic use*
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D047908:Intracellular Signaling Peptides and Proteins; C000619710:MARCKS protein, human; C483227:MARCKS-related peptide; C000619711:Marcks protein, mouse; D008565:Membrane Proteins; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D050257:Tubulin Modulators; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D017239:Paclitaxel
keywords: MANS peptide; breast cancer; mitotic inhibitor; paclitaxel; phospho-MARCKS