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PPARγ-inactive Δ2-troglitazone independently triggers ER stress and apoptosis in breast cancer cells

Authors
  • Colin-Cassin, Christelle
  • Yao, Xiao
  • Claudia Cerella
  • Chbicheb, Sarra
  • Kuntz, Sandra
  • Mazerbourg, Sabine
  • Boisbrun, Michel
  • Chapleur, Yves
  • Marc Diederich
  • Flament, Stephane
  • Grillier-Vuissoz, Isabelle
Type
Published Article
Journal
Molecular Carcinogenesis
Publisher
Wiley (John Wiley & Sons)
Publication Date
Nov 30, 2013
Volume
54
Issue
5
Identifiers
DOI: 10.1002/mc.22109
Source
LBMCC
Keywords
License
Yellow

Abstract

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 pancreatic endoplasmic reticulum kinase-like endoplasmic reticulum kinase (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.

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