PLoS ONE (Jan 2013)

OBATOCLAX and ABT-737 induce ER stress responses in human melanoma cells that limit induction of apoptosis.

  • David Wroblewski,
  • Chen Chen Jiang,
  • Amanda Croft,
  • Margaret L Farrelly,
  • Xu Dong Zhang,
  • Peter Hersey

DOI
https://doi.org/10.1371/journal.pone.0084073
Journal volume & issue
Vol. 8, no. 12
p. e84073

Abstract

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Anti-apoptotic Bcl-2 family proteins, in particular, Mcl-1, are known to play a critical role in resistance of human melanoma cells to induction of apoptosis by endoplasmic reticulum stress and other agents. The present study examined whether the BH3 mimetics, Obatoclax and ABT-737, which inhibit multiple anti-apoptotic Bcl-2 family proteins, would overcome resistance to apoptosis. We report that both agents induced a strong unfolded protein response (UPR) and that RNAi knockdown of UPR signalling proteins ATF6, IRE1α and XBP-1 inhibited Mcl-1 upregulation and increased sensitivity to the agents. These results demonstrate that inhibition of anti-apoptotic Bcl-2 proteins by Obatoclax and ABT-737 appears to elicit a protective feedback response in melanoma cells, by upregulation of Mcl-1 via induction of the UPR. We also report that Obatoclax, but not ABT-737, strongly induces autophagy, which appears to play a role in determining melanoma sensitivity to the agents.