The anti-apoptotic proteins Bcl-2 and Bcl-xL suppress Beclin 1/Atg6-mediated lethal autophagy in polyploid cells

Exp Cell Res. 2020 Sep 1;394(1):112112. doi: 10.1016/j.yexcr.2020.112112. Epub 2020 May 27.

Abstract

Inhibition of Aurora-B kinase is a synthetic lethal therapy for tumors that overexpress the MYC oncoprotein. It is currently unclear whether co-occurring oncogenic alterations might influence this synthetic lethality by conferring more or less potency in the killing of tumor cells. To identify such modifiers, isogenic cell lines were utilized to test a variety of cancer genes that have been previously demonstrated to promote survival under conditions of cellular stress, contribute to chemoresistance and/or suppress MYC-primed apoptosis. It was found that Bcl-2 and Bcl-xL, two antiapoptotic members of the Bcl-2 family, can partially suppress the synthetic lethality, but not multinucleation, elicited by a pan-aurora kinase inhibitor, VX-680. Suppression was show to stem from the inhibition of autophagy, specifically in multinucleated cells, rather than a general inhibition of apoptosis. The anti-autophagic activity of Bcl-2 also impacted polyploid cell recovery in colony-forming assays, suggesting a route of escape from MYC-VX-680 synthetic lethality that may have clinical consequences. These findings expand on previous conclusions that autophagic death of VX-680-induced polyploid cells is mediated by Atg6. Bcl-2 and Bcl-xL negatively modulate MYC-VX-680 synthetic lethality and it is the anti-autophagic activity of these two Bcl-2 family proteins, specifically in multinucleate cells, that contributes to resistance to Aurora kinase-targeting drugs.

Keywords: AURKB; Apoptosis; Autophagy; Bcl-2; Bcl-xL; MYC; VX-680.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • Autophagy / physiology*
  • Beclin-1 / genetics
  • Beclin-1 / metabolism*
  • Cell Line, Tumor
  • Humans
  • Membrane Proteins / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • bcl-X Protein / metabolism*

Substances

  • Apoptosis Regulatory Proteins
  • BCL2 protein, human
  • BCL2L1 protein, human
  • BECN1 protein, human
  • Beclin-1
  • Membrane Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • bcl-X Protein