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PPARγ‐inactive Δ2‐troglitazone independently triggers ER stress and apoptosis in breast cancer cells
Author(s) -
ColinCassin Christelle,
Yao Xiao,
Cerella Claudia,
Chbicheb Sarra,
Kuntz Sandra,
Mazerbourg Sabine,
Boisbrun Michel,
Chapleur Yves,
Diederich Marc,
Flament Stephane,
GrillierVuissoz Isabelle
Publication year - 2015
Publication title -
molecular carcinogenesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.254
H-Index - 97
eISSN - 1098-2744
pISSN - 0899-1987
DOI - 10.1002/mc.22109
Subject(s) - unfolded protein response , endoplasmic reticulum , biology , xbp1 , microbiology and biotechnology , cancer research , biochemistry , rna splicing , rna , gene
Our aim was to better understand peroxisome proliferator‐activated receptor gamma (PPARγ)‐independent pathways involved in anti‐cancer effects of thiazolidinediones (TZDs). We focused on Δ2‐troglitazone (Δ2‐TGZ), a PPARγ inactive TZD that affects breast cancer cell viability. Appearance of TUNEL positive cells, changes in mitochondrial membrane potential, cleavage of poly(ADP‐ribose) polymerase (PARP)‐1 and caspase‐7 revealed that apoptosis occurred in both hormone‐dependent MCF7 and hormone‐independent MDA‐MB‐231 breast cancer cells after 24 and 48 h of treatment. A microarray study identified endoplasmic reticulum (ER) stress as an essential cellular function since many genes involved in ER stress were upregulated in MCF7 cells following Δ2‐TGZ treatment. Δ2‐TGZ‐induced ER stress was further confirmed in MCF7 cells by phosphorylation of p ancreatic endoplasmic reticulum kinase‐like e ndoplasmic r eticulum k inase (PERK) and its target eIF2α after 1.5 h, rapid increase in activating transcription factor (ATF) 3 mRNA levels, splicing of X‐box binding protein 1 (XBP1) after 3 h, accumulation of binding immunogloblulin protein (BiP) and CCAAT‐enhancer‐binding protein homologous protein (CHOP) after 6 h. Immunofluorescence microscopy indicated that CHOP was relocalized to the nucleus of treated cells. Similarly, in MDA‐MB‐231 cells, overexpression of ATF3, splicing of XBP1, and accumulation of BiP and CHOP were observed following Δ2‐TGZ treatment. In MCF7 cells, knock‐down of CHOP or the inhibition of c‐Jun N‐terminal kinase (JNK) did not impair cleavage of PARP‐1 and caspase‐7. Altogether, our results show that ER stress is an early response of major types of breast cancer cells to Δ2‐TGZ, prior to, but not causative of apoptosis. © 2013 Wiley Periodicals, Inc.