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Bid mediates anti-apoptotic COX-2 induction through the IKKbeta/NFkappaB pathway due to 5-MCDE exposure

Wenjing Luo1, Jingxia Li, Dongyun Zhang

  • 1Nelson Institute of Environmental Medicine, New York University School of Medicine, 57 Old Forge Road, Tuxedo, NY 10987, USA.

Current Cancer Drug Targets
|January 22, 2010
PubMed

Insights

Bid protein promotes cell survival against 5-MCDE exposure by upregulating COX-2 via the IKKbeta/NFkappaB pathway. Bid knockout MEFs show increased apoptosis, highlighting Bid

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Biochemistry

Background:

  • Bid is traditionally known as a pro-apoptotic mediator.
  • Emerging evidence suggests a potential role for Bid in cell survival.
  • The role of Bid in response to environmental toxins like 5-MCDE is not fully understood.

Purpose of the Study:

  • To investigate the role of Bid in mouse embryonic fibroblasts (MEFs) exposed to low doses of 5-MCDE.
  • To elucidate the molecular mechanisms underlying Bid's function in 5-MCDE-induced cellular responses.
  • To determine if Bid exhibits anti-apoptotic functions in this context.

Main Methods:

  • Comparison of apoptotic responses in wild-type (WT) MEFs and Bid knockout (Bid(-/-)) MEFs upon 5-MCDE exposure.
  • Re-constitution of Bid expression in Bid(-/-) cells to assess its functional impact.
  • Analysis of Cyclooxygenase-2 (COX-2) expression and its correlation with Bid's function.
  • Investigation of the involvement of the IKKbeta/NFkappaB signaling pathway using knockout and knockdown approaches.

Main Results:

  • Bid knockout MEFs exhibited significantly increased apoptosis in response to 0.25 microM 5-MCDE compared to WT MEFs.
  • Re-introduction of Bid into Bid(-/-) cells restored resistance to 5-MCDE-induced apoptosis.
  • Bid's anti-apoptotic effect was linked to the induction of COX-2 expression, as COX-2 knockdown sensitized WT MEFs to 5-MCDE.
  • Bid mediated COX-2 induction through the IKKbeta/NFkappaB pathway; Bid deficiency blocked IKK/NFkappaB activation, and IKKbeta knockout abrogated 5-MCDE-induced COX-2.

Conclusions:

  • Bid plays a critical anti-apoptotic role in MEFs exposed to low-dose 5-MCDE.
  • Bid mediates its cell-survival function by inducing COX-2 expression via the IKKbeta/NFkappaB signaling pathway.
  • These findings reveal a novel pro-survival mechanism involving Bid in response to chemical carcinogens.

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