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Nonredundant role of Bax and Bak in Bid-mediated apoptosis

Pierre-François Cartron1, Philippe Juin, Lisa Oliver

  • 1INSERM U419, IFR 26, 44035 Nantes Cedex 01. Clinique Universitaire de Neurochirurgie, Hôpital G & R Laennec, CHU Nantes, 44093 Nantes Cedex 01, France.

Molecular and Cellular Biology
|June 17, 2003
PubMed

Insights

Bax and Bak proteins are crucial for apoptosis and hindering tumor growth. In human glioblastoma, Bax deficiency is often compensated by increased Bak, severely impairing the cell death program when both are absent.

Area of Science:

  • Cell Biology
  • Cancer Research
  • Molecular Biology

Background:

  • Bax and Bak are pro-apoptotic proteins critical for programmed cell death.
  • Their role in tumorigenesis suggests they can act as tumor suppressors.
  • Understanding their function in human cancers like glioblastoma is essential.

Purpose of the Study:

  • To investigate the expression and function of Bax and Bak proteins in human glioblastoma multiforme (GBM).
  • To determine the impact of Bax and Bak deficiency on GBM apoptosis and tumor growth.
  • To elucidate the differential roles of Bax and Bak in response to various apoptotic stimuli.

Main Methods:

  • Analysis of Bax and Bak protein expression in 50 human GBM tumors.
  • In vitro studies using Bax-deficient and Bax-expressing GBM cell lines.
  • Generation of Bak-deficient GBM cells using an antisense strategy.
  • Assessment of apoptosis induction by various stimuli (UV, staurosporine, doxorubicin, caspase 8, granzyme B).
  • Evaluation of tumor clonogenicity and growth in vivo.

Main Results:

  • All GBM tumors expressed Bak; three lacked Bax expression.
  • Bax-deficient GBM cells showed increased resistance to apoptosis compared to Bax-expressing cells.
  • Bak deficiency rendered cells resistant to caspase 8 but not granzyme B-induced apoptosis.
  • Complete resistance to all apoptotic stimuli was observed in cells lacking both Bax and Bak.
  • GrB-cleaved Bid and C8-cleaved Bid utilize Bax and Bak, respectively, for mitochondrial cytochrome c release.
  • Bax/Bak deficiency did not affect tumor clonogenicity or growth in mice.

Conclusions:

  • Bax deficiency in GBM is compensated by increased Bak expression.
  • Double deficiency of Bax and Bak severely impairs the apoptotic program in human cancer.
  • This study reveals the distinct roles of Bax and Bak in mediating apoptosis via different pathways.

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