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A role for mitochondrial Bak in apoptotic response to anticancer drugs

G Q Wang1, B R Gastman, E Wieckowski

  • 1Department of Pathology, The University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, USA.

The Journal of Biological Chemistry
|July 12, 2001
PubMed

Insights

Bak protein is crucial for initiating apoptosis by enabling cytochrome c release from mitochondria. Its absence confers chemoresistance in T leukemic cells, highlighting Bak

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Cancer Research

Background:

  • Apoptosis, or programmed cell death, is a critical process in multicellular organisms.
  • Mitochondria play a central role in the intrinsic apoptotic pathway.
  • Cytochrome c release from mitochondria is a key event triggering apoptosis.

Purpose of the Study:

  • To investigate the specific role of Bak, a Bcl-2 family protein, in cytochrome c release.
  • To determine if Bak deficiency contributes to chemoresistance in human T leukemic cells.

Main Methods:

  • Utilized a clonal Jurkat T leukemic cell line engineered to be deficient in Bak expression.
  • Assessed apoptosis induction via various stimuli (UV, anticancer drugs) in Bak-deficient vs. wild-type cells.
  • Examined mitochondrial function, cytochrome c release, and caspase activation.
  • Restored Bak expression and function through gene transduction and recombinant protein addition.

Main Results:

  • Bak-deficient cells exhibited resistance to apoptosis induced by multiple stimuli.
  • These cells failed to release cytochrome c from mitochondria, indicating a block at the mitochondrial level.
  • Restoring Bak expression or adding recombinant Bak protein rescued the apoptotic phenotype and restored cytochrome c release.
  • Bak's function in cytochrome c release was independent of Bid and Bax proteins.

Conclusions:

  • Bak is essential for the mitochondrial release of cytochrome c, a critical step in apoptosis.
  • Bak deficiency confers chemoresistance in human T leukemic cells.
  • Targeting Bak may represent a therapeutic strategy to overcome chemoresistance in T leukemias.

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