Role of bile salt in regulating Mcl-1 phosphorylation and chemoresistance in hepatocellular carcinoma cells

• Type of Material: Article
• Authors: Mingmei Liao, Central South University, China; Jinfeng Zhao, Central South University, China; Ton Wang, Emory University; Jinghua Duan, Central South University, China; Yangde Zhang, Central South University, China; Xingming Deng, Emory University
• Language: English
• Date: 2011-04-20
• Publisher: BioMed Central
• Publication Version: Final Published Version
• Copyright Statement: © 2011 Liao et al; licensee BioMed Central Ltd.
• License: Creative Commons Attribution 2.0 Generic
• Final Published Version (URL): http://www.molecular-cancer.com/content/10/1/44
• Title of Journal or Parent Work: Molecular Cancer
• ISSN: 1476-4598
• Volume: 10
• Issue: 44
• Start Page: 1
• End Page: 9
• Grant/Funding Information: This work was supported by a Lotus Scholars Program (200734), by a Flight Attendant Medical Research Institute Clinical Innovator Award and by the Howard Hughes Medical Institute (HHMI) Science for Life Extramural Research Award (to TW).
• Research Categories: Health Sciences, Oncology

Abstract

Background Glycochenodeoxycholate (GCDA) is one of the major human bile salts. Bile salts stimulate cell survival and proliferation through the mitogen-activated protein kinase, but the downstream signaling mechanism(s) remains enigmatic. Mcl-1 is an antiapoptotic molecule of the Bcl2 family that is extensively overexpressed in tumor tissues of patients with hepatocellular carcinoma (HCC). Results Here we found that exposure of HepG2 cells to GCDA results in activation of ERK1 and ERK2 and phosphorylation of Mcl-1 in a PD98059 (MEK inhibitor)-sensitive manner. GCDA stimulates Mcl-1 phosphorylation in cells expressing WT but not T163A Mcl-1 mutant, indicating that GCDA-induced Mcl-1 phosphorylation occurs exclusively at the T163 site in its PEST region. GCDA-induced Mcl-1 phosphorylation at T163 enhances the half-life of Mcl-1. Treatment of HepG2 cells with GCDA facilitates Mcl-1 dissociation from Mule (a physiological Mcl-1 ubiquitin E3 ligase). Specific depletion of Mcl-1 from HepG2 cells by RNA interference increases sensitivity of HepG2 cells to chemotherapeutic drugs (i.e. cisplatin and irinotecan). In addition to activation of the ERK/Mcl-1 survival pathway, GCDA can also induce dose-dependent apurinic/apyrimidinic (AP) sites of DNA lesions, which may partially neutralize its survival activity. Conclusion Our findings suggest that bile salt may function as a survival agonist and/or potential carcinogen in the development of HCC. Molecular approaches that inactivate Mcl-1 by blocking its T163 phosphorylation may represent new strategies for treatment of HCC.