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Published on: October 5, 2012

Bak functionally complements for loss of Bax during p14ARF-induced mitochondrial apoptosis in human cancer cells

P G Hemmati1, D Güner, B Gillissen

  • 1Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Berlin-Buch, Germany.

Oncogene
|July 19, 2006
PubMed

Insights

p14(ARF) induces apoptosis through the mitochondrial pathway, primarily via Bak, independent of p53 and Bax in some cancer cells. A portion of p14(ARF)-mediated cell death and growth inhibition occurs independently of Bax and Bak.

Area of Science:

  • Cell Biology
  • Molecular Oncology
  • Apoptosis Signaling

Background:

  • The tumor suppressor p14(ARF) was initially thought to function solely through the mdm-2/p53 pathway.
  • Previous research demonstrated p14(ARF) can induce apoptosis independently of p53 and Bax.
  • The precise mechanisms and dependencies of p14(ARF)-induced apoptosis, particularly involving mitochondrial pathways and Bcl-2 family proteins, require further elucidation.

Purpose of the Study:

  • To investigate the role of Bak and Bax in p14(ARF)-induced apoptosis.
  • To determine the contribution of the mitochondrial pathway (cytochrome c release, caspase activation) to p14(ARF)-mediated cell death.
  • To explore p14(ARF)-induced apoptosis and growth inhibition in cells with varying p53 and Bax/Bak status.

Main Methods:

  • Utilized p53/Bax-deficient DU145 prostate cancer cells and isogenic p53-proficient/deficient HCT116 colon cancer cells.
  • Employed short interference RNA (siRNA) to knock down Bak expression.
  • Assessed mitochondrial membrane potential, cytochrome c release, and caspase-9/caspase-3/7 activities following p14(ARF) expression.

Main Results:

  • p14(ARF) induced mitochondrial membrane potential breakdown and cytochrome c release in DU145 cells, activating caspases.
  • p14(ARF)-induced apoptosis in DU145 cells relied on Bak but not Bax; Bax re-expression offered no additional benefit.
  • In HCT116 cells, combined Bax and Bak deficiency attenuated p14(ARF)-induced apoptosis, cytochrome c release, and caspase activation, while single knockdowns had minimal effect.
  • A significant portion of p14(ARF)-induced cell death and inhibition of clonogenic growth occurred independently of Bax and Bak.

Conclusions:

  • p14(ARF) triggers apoptosis via a Bax/Bak-dependent mitochondrial pathway in p53-proficient cells, with Bax being dispensable in p53-deficient cells.
  • Bak plays a primary role in p14(ARF)-induced apoptosis in p53-deficient prostate cancer cells.
  • p14(ARF) mediates substantial cell death and inhibits growth through mechanisms independent of the Bax/Bak pathway.

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