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

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Christelle Colin-Cassin1, Xiao Yao, Claudia Cerella

  • 1Université de Lorraine, CRAN, UMR 7039, Vandœuvre-lès-Nancy, France; CNRS, CRAN, UMR 7039, Vandœuvre-lès-Nancy, France.

Molecular Carcinogenesis
|December 3, 2013
PubMed

Insights

Thiazolidinediones (TZDs) induce apoptosis in breast cancer cells via endoplasmic reticulum (ER) stress. This ER stress response occurs early, preceding apoptosis, but does not directly cause it, revealing novel anti-cancer pathways.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Thiazolidinediones (TZDs) are known for their anti-cancer properties, but the underlying mechanisms beyond PPARγ activation are not fully understood.
  • Investigating PPARγ-independent pathways is crucial for developing novel anti-cancer therapeutics.

Purpose of the Study:

  • To elucidate the PPARγ-independent anti-cancer effects of thiazolidinediones (TZDs) by focusing on Δ2-troglitazone (Δ2-TGZ).
  • To investigate the role of endoplasmic reticulum (ER) stress in mediating the anti-cancer effects of Δ2-TGZ in breast cancer cells.

Main Methods:

  • Treatment of MCF7 and MDA-MB-231 breast cancer cells with Δ2-TGZ.
  • Assessment of apoptosis using TUNEL assay, mitochondrial membrane potential, and PARP-1/caspase-7 cleavage.
  • Microarray analysis to identify cellular pathways affected by Δ2-TGZ.
  • Confirmation of ER stress markers including PERK, eIF2α, ATF3, XBP1, BiP, and CHOP.
  • Immunofluorescence microscopy for CHOP localization.
  • Gene knockdown (CHOP) and inhibitor studies (JNK).

Main Results:

  • Δ2-TGZ induced apoptosis in both hormone-dependent (MCF7) and hormone-independent (MDA-MB-231) breast cancer cells.
  • Microarray and subsequent validation confirmed ER stress as an early response to Δ2-TGZ, evidenced by upregulation of ER stress genes and key protein markers.
  • ER stress markers (PERK, eIF2α, ATF3, XBP1, BiP, CHOP) were rapidly activated in both cell lines.
  • CHOP relocalization to the nucleus was observed.
  • CHOP knockdown or JNK inhibition did not prevent apoptosis, indicating ER stress precedes but is not causative of apoptosis.

Conclusions:

  • Endoplasmic reticulum (ER) stress is an early, conserved response in major breast cancer subtypes treated with Δ2-TGZ.
  • This ER stress response occurs prior to the induction of apoptosis but is not the direct cause of apoptotic cell death.
  • These findings highlight a novel PPARγ-independent mechanism of TZD anti-cancer activity involving ER stress.
Keywords:
apoptosisbreast cancerendoplasmic reticulum stressthiazolidinediones

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