title: PPARγ-inactive Δ2-troglitazone independently triggers ER stress and apoptosis in breast cancer cells.
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.
authors.affiliation: Université de Lorraine, CRAN, UMR 7039, Vandœuvre-lès-Nancy, France; CNRS, CRAN, UMR 7039, Vandœuvre-lès-Nancy, France.
authors.forename: Christelle
authors.initials: C
authors.lastname: Colin-Cassin
authors.forename: Xiao
authors.initials: X
authors.lastname: Yao
authors.forename: Claudia
authors.initials: C
authors.lastname: Cerella
authors.forename: Sarra
authors.initials: S
authors.lastname: Chbicheb
authors.forename: Sandra
authors.initials: S
authors.lastname: Kuntz
authors.forename: Sabine
authors.initials: S
authors.lastname: Mazerbourg
authors.forename: Michel
authors.initials: M
authors.lastname: Boisbrun
authors.forename: Yves
authors.initials: Y
authors.lastname: Chapleur
authors.forename: Marc
authors.initials: M
authors.lastname: Diederich
authors.forename: Stephane
authors.initials: S
authors.lastname: Flament
authors.forename: Isabelle
authors.initials: I
authors.lastname: Grillier-Vuissoz
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D053179:Caspase 7 / Q000235:genetics / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002839:Chromans / Q000737:chemistry / Q000494:pharmacology*; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects*; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D020287:In Situ Nick-End Labeling; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011065:Poly(ADP-ribose) Polymerases / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D045162:Thiazolidinediones / Q000737:chemistry / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000235:genetics / Q000378:metabolism; D000077288:Troglitazone; D014407:Tumor Cells, Cultured
chemical_list: D014408:Biomarkers, Tumor; D002839:Chromans; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D012333:RNA, Messenger; D045162:Thiazolidinediones; D051742:Transcription Factor CHOP; D011065:Poly(ADP-ribose) Polymerases; D048031:JNK Mitogen-Activated Protein Kinases; D053179:Caspase 7; D000077288:Troglitazone
keywords: apoptosis; breast cancer; endoplasmic reticulum stress; thiazolidinediones