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Oligomycin A enhances apoptotic effect of TRAIL through CHOP-mediated death receptor 5 expression

Long He1, Jae Hyuk Jang, Hyun Gil Choi

  • 1Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, South Korea.

Molecular Carcinogenesis
|January 22, 2013
PubMed

Insights

Oligomycin A enhances cancer cell death by increasing sensitivity to TRAIL-induced apoptosis. This occurs through endoplasmic reticulum stress, leading to CHOP-mediated DR5 upregulation and promoting programmed cell death.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • TRAIL resistance is a major challenge in cancer therapy.
  • Previous studies showed oligomycin suppressed TNF-induced apoptosis, but its effect on TRAIL-induced apoptosis was unclear.

Purpose of the Study:

  • To identify small molecules that enhance cancer cell death induced by TRAIL.
  • To elucidate the mechanism by which oligomycin A sensitizes cancer cells to TRAIL.

Main Methods:

  • Screening of small molecules for TRAIL-sensitizing effects.
  • Investigating the role of endoplasmic reticulum stress (ER-stress) signaling pathways.
  • Analyzing CCAAT/enhancer-binding protein homologous protein (CHOP) and death receptor 5 (DR5) expression.
  • Utilizing small-interfering RNA (siRNA) to knock down CHOP.

Main Results:

  • Oligomycin A (OMA) was identified as a sensitizer of HeLa cells to TRAIL-induced apoptosis.
  • OMA triggered the inositol-requiring enzyme 1 (IRE1) pathway, leading to ER-stress, XBP1 splicing, CHOP expression, and DR5 upregulation.
  • CHOP was confirmed to bind the DR5 promoter, sensitizing cells to TRAIL.
  • CHOP knockdown abrogated OMA's sensitization effect.

Conclusions:

  • OMA enhances TRAIL-induced apoptosis in cervical cancer cells.
  • The mechanism involves OMA-induced ER-stress, leading to CHOP-mediated DR5 upregulation.
  • This study identifies a novel strategy to overcome TRAIL resistance in cancer treatment.

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