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Obatoclax induces Atg7-dependent autophagy independent of beclin-1 and BAX/BAK

F McCoy1, J Hurwitz, N McTavish

  • 1Centre for Cancer Research and Cell Biology, Queen's University Belfast, Northern Ireland, UK.

Cell Death & Disease
|March 4, 2011
PubMed

Insights

Obatoclax, a BCL-2 inhibitor, causes cancer cell death through both BAX/BAK-dependent apoptosis and BAX/BAK-independent mechanisms, including autophagy. Resistance involves pathways beyond apoptosis and autophagy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Biology

Background:

  • Targeting the anti-apoptotic B-cell lymphoma-2 (BCL-2) family is a key cancer therapy strategy.
  • Obatoclax is a BCL-2 inhibitor in clinical development.

Purpose of the Study:

  • To investigate the mechanisms of obatoclax-induced cell death and toxicity.
  • To explore the roles of BCL-2 family proteins, apoptosis, and autophagy in obatoclax efficacy.

Main Methods:

  • Utilized BAX/BAK knockout and beclin-1/Atg7 silenced cells.
  • Assessed apoptosis, clonogenicity, LC3 processing, and ultrastructural changes.
  • Investigated obatoclax resistance mechanisms.

Main Results:

  • Obatoclax induced BAX/BAK-dependent apoptosis but also caused toxicity independent of apoptosis.
  • Obatoclax triggered autophagy-like responses (LC3 processing, vacuolation) and S6 kinase inhibition.
  • Autophagy inhibition (Atg7 knockout) did not fully prevent obatoclax toxicity or clonogenicity loss.
  • Obatoclax resistance involved mechanisms beyond apoptosis and autophagy.

Conclusions:

  • Obatoclax exhibits multifaceted toxicity, involving both BCL-2 family-dependent and -independent pathways.
  • Autophagy is activated by obatoclax but is not the sole mediator of its cytotoxic effects.
  • Novel resistance mechanisms contribute to obatoclax efficacy, suggesting complex therapeutic strategies.

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