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Mcl-1 down-regulation potentiates ABT-737 lethality by cooperatively inducing Bak activation and Bax translocation

Shuang Chen1, Yun Dai, Hisashi Harada

  • 1Department of Medicine, Virginia Commonwealth University and Massey Cancer Center, Richmond, Virginia 23298, USA.

Cancer Research
|January 20, 2007
PubMed

Insights

Targeting Mcl-1 with CDK inhibitors enhances ABT-737

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cell Death Pathways

Background:

  • Bcl-2 family proteins regulate apoptosis.
  • ABT-737 targets Bcl-2 and Bcl-xL, but resistance can occur due to Mcl-1.
  • Mcl-1 is implicated in resistance to Bcl-2 antagonists.

Purpose of the Study:

  • To investigate if down-regulating Mcl-1 enhances ABT-737 efficacy in leukemia.
  • To elucidate the molecular mechanisms by which Mcl-1 down-regulation affects apoptosis induction by ABT-737.

Main Methods:

  • Utilized cyclin-dependent kinase (CDK) inhibitor roscovitine and Mcl-1-shRNA to down-regulate Mcl-1.
  • Employed Bax and Bak knockout mouse embryonic fibroblasts (MEFs).
  • Assessed Bax conformational change, Bak activation, Bax translocation, and apoptosis.

Main Results:

  • Mcl-1 down-regulation significantly increased ABT-737-induced lethality in human leukemia cells.
  • Combined roscovitine and ABT-737 treatment unleashed Bak from Bcl-xL and Mcl-1, activating Bak and promoting Bax translocation.
  • Bax was essential for ABT-737+/-roscovitine lethality, while Bak potentiated apoptosis when Mcl-1 was downregulated.

Conclusions:

  • Mcl-1 down-regulation by CDK inhibitors or genetic methods potentiates ABT-737 lethality.
  • This potentiation involves cooperative interactions, including Bak release and activation, and Bax translocation.
  • Findings provide a rationale for co-targeting Mcl-1 and Bcl-2/Bcl-xL in leukemia treatment.

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