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S1 kills MCF-7/ADR cells more than MCF-7 cells: A protective mechanism of endoplasmic reticulum stress

Ting Song1, Furong Liang, Zhichao Zhang

  • 1State Key Laboratory of Fine Chemicals, School of Chemistry, Dalian University of Technology, Dalian, China.

Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie
|April 23, 2013
PubMed

Insights

Pan-BH3 mimetic S1 effectively targets drug-resistant breast cancer cells. Defective endoplasmic reticulum (ER) stress in these cells enhances their sensitivity to S1-induced apoptosis.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Death Mechanisms

Background:

  • Chemotherapy resistance in breast cancer is linked to P-glycoprotein (P-gp) and endoplasmic reticulum (ER) stress.
  • Understanding resistance mechanisms is crucial for developing effective breast cancer therapies.

Purpose of the Study:

  • To evaluate the efficacy of the pan-BH3 mimetic S1 on drug-resistant MCF-7/ADR breast cancer cells.
  • To investigate the role of S1-induced ER stress in mediating cell death in these resistant cells.

Main Methods:

  • Treatment of MCF-7 and MCF-7/ADR cells with pan-BH3 mimetic S1.
  • Assessment of mitochondrial apoptosis via Bax/Bak activation and cytochrome c release.
  • Analysis of ER stress response pathways (IRE1, JNK, ERK) and Bcl-2 phosphorylation using coimmunoprecipitation and western blotting.
  • Evaluation of synergistic effects with ERK inhibitor PD98059.

Main Results:

  • S1 induced faster and greater mitochondrial apoptosis in drug-resistant MCF-7/ADR cells compared to MCF-7 cells.
  • P-glycoprotein had minimal impact on S1's cellular entry and target engagement.
  • S1 triggered an IRE1-mediated ER stress response and JNK/ERK activation in sensitive MCF-7 cells, but not in resistant MCF-7/ADR cells.
  • ER stress protected against S1-induced apoptosis by promoting Bcl-2 phosphorylation, sequestering pro-apoptotic proteins.
  • Defective ER stress in MCF-7/ADR cells correlated with increased sensitivity to S1.

Conclusions:

  • Pan-BH3 mimetic S1 demonstrates significant efficacy against P-gp-mediated drug-resistant breast cancer cells.
  • ER stress plays a protective role in S1-induced apoptosis, and its absence in resistant cells enhances sensitivity.
  • Targeting ER stress pathways may offer novel therapeutic strategies for overcoming chemotherapy resistance in breast cancer.
Keywords:
ApoptosisBH3 mimeticER stressMCF-7/ADRPBcl-2

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