Journal
MOLECULAR CARCINOGENESIS
Volume 54, Issue 5, Pages 393-404Publisher
WILEY-BLACKWELL
DOI: 10.1002/mc.22109
Keywords
thiazolidinediones; breast cancer; endoplasmic reticulum stress; apoptosis
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Funding
- Universite de Lorraine
- Conseil Regional de Lorraine
- Ligue Contre le Cancer
- Fondation de Recherche Cancer et Sang
- Recherches Scientifiques Luxembourg Association
- Een Haerz fir kriibskrank Kanner Association
- Action Lions Vaincre le Cancer Association
- European Union [ITN RedCat 215009]
- Televie Luxembourg
- National Research Foundation (NRF)
- MEST of Korea for Tumor Microenvironment Global Core Research Center (GCRC) [2012-0001184]
- Seoul National University Research Grant
- Research Settlement Fund
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Our aim was to better understand peroxisome proliferator-activated receptor gamma (PPAR)-independent pathways involved in anti-cancer effects of thiazolidinediones (TZDs). We focused on 2-troglitazone (2-TGZ), a PPAR 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 48h 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 2-TGZ treatment. 2-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 eIF2 after 1.5h, rapid increase in activating transcription factor (ATF) 3 mRNA levels, splicing of X-box binding protein 1 (XBP1) after 3h, accumulation of binding immunogloblulin protein (BiP) and CCAAT-enhancer-binding protein homologous protein (CHOP) after 6h. 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 2-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 2-TGZ, prior to, but not causative of apoptosis. (c) 2013 Wiley Periodicals, Inc.
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