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

Mol Carcinog. 2015 May;54(5):393-404. doi: 10.1002/mc.22109. Epub 2013 Nov 30.


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.

Keywords: apoptosis; breast cancer; endoplasmic reticulum stress; thiazolidinediones.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects*
  • Biomarkers, Tumor
  • Blotting, Western
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Caspase 7 / genetics
  • Caspase 7 / metabolism
  • Cell Cycle / drug effects
  • Cell Proliferation / drug effects
  • Chromans / chemistry
  • Chromans / pharmacology*
  • Endoplasmic Reticulum / drug effects*
  • Endoplasmic Reticulum / metabolism
  • Endoplasmic Reticulum Stress / drug effects*
  • Female
  • Fluorescent Antibody Technique
  • Humans
  • Hypoglycemic Agents / pharmacology*
  • In Situ Nick-End Labeling
  • JNK Mitogen-Activated Protein Kinases / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • PPAR gamma / antagonists & inhibitors*
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Phosphorylation / drug effects
  • Poly(ADP-ribose) Polymerases / genetics
  • Poly(ADP-ribose) Polymerases / metabolism
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / drug effects
  • Thiazolidinediones / chemistry
  • Thiazolidinediones / pharmacology*
  • Transcription Factor CHOP / genetics
  • Transcription Factor CHOP / metabolism
  • Troglitazone
  • Tumor Cells, Cultured


  • Biomarkers, Tumor
  • Chromans
  • Hypoglycemic Agents
  • PPAR gamma
  • RNA, Messenger
  • Thiazolidinediones
  • Transcription Factor CHOP
  • Poly(ADP-ribose) Polymerases
  • JNK Mitogen-Activated Protein Kinases
  • Caspase 7
  • Troglitazone