title: S1 kills MCF-7/ADR cells more than MCF-7 cells: A protective mechanism of endoplasmic reticulum stress.
abstract: Drug resistance in chemotherapy for breast cancer is associated with high levels of P-glycoprotein (P-gp) as well as endoplasmic reticulum (ER) stress. In this paper, we aimed to evaluate the efficacy of a pan-BH3 mimetic S1 on drug-resistant MCF-7/ADR cells, and the roles of S1-induced ER stress in cell death. S1 exhibited greater and faster mitochondrial apoptosis in MCF-7/ADR cells than in MCF-7 cells. We demonstrated by Bax/Bak activation and cyrochrome c release that the p-glycprotein had little influence on S1 entering cells and hitting its targets in MCF-7/ADR cells. An IRE1-mediated ER stress response followed by c-Jun N-terminal kinase (JNK) and extracellular signal-regulated protein kinase (ERK) activation was specifically induced by S1 in MCF-7 cells, but not in MCF-7/ADR cells. Coimmunoprecipitation and western blotting analysis determined that ER stress played a protective role in S1-induced apoptosis by triggering Bcl-2 phosphorylation, which grabbed more pro-apoptotic proteins. The synergism effect of ERK inhibitor PD98059 with S1 confirmed the protective role of ER stress. Defective ER stress in MCF-7/ADR cells confers the more sensitivity toward S1.
authors.affiliation: State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Song
authors.forename: Furong
authors.initials: F
authors.lastname: Liang
authors.forename: Zhichao
authors.initials: Z
authors.lastname: Zhang
authors.forename: Yubo
authors.initials: Y
authors.lastname: Liu
authors.forename: Hongkun
authors.initials: H
authors.lastname: Sheng
authors.forename: Mingzhou
authors.initials: M
authors.lastname: Xie
mesh_terms: D000073:Acenaphthenes / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D015153:Blotting, Western; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D006801:Humans; D047468:Immunoprecipitation; D061986:MCF-7 Cells; D010766:Phosphorylation; D011758:Pyrroles / Q000494:pharmacology*
chemical_list: C557101:8-oxo-3-thiomorpholin-4-yl-8H-acenaphtho(1,2-b)pyrrole-9-carbonitrile; D000073:Acenaphthenes; D000970:Antineoplastic Agents; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D011758:Pyrroles
keywords: Apoptosis; BH3 mimetic; ER stress; MCF-7/ADR; PBcl-2