PPARgamma-inactive Delta2-troglitazone independently triggers ER stress and apoptosis in breast cancer cells.
Fiche publication
Date publication
mai 2015
Auteurs
Membres identifiés du Cancéropôle Est :
Pr FLAMENT Stéphane, Dr GRILLIER-VUISSOZ Isabelle, Dr KUNTZ Sandra, Dr MAZERBOURG Sabine
Tous les auteurs :
Colin-Cassin C, Yao X, Cerella C, Chbicheb S, Kuntz S, Mazerbourg S, Boisbrun M, Chapleur Y, Diederich M, Flament S, Grillier-Vuissoz I
Lien Pubmed
Résumé
Our aim was to better understand peroxisome proliferator-activated receptor gamma (PPARgamma)-independent pathways involved in anti-cancer effects of thiazolidinediones (TZDs). We focused on Delta2-troglitazone (Delta2-TGZ), a PPARgamma 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 Delta2-TGZ treatment. Delta2-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 eIF2alpha 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 Delta2-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 Delta2-TGZ, prior to, but not causative of apoptosis.
Référence
Mol Carcinog. 2015 May;54(5):393-404