Mode of cell death induced by the HSP90 inhibitor 17-AAG (tanespimycin) is dependent on the expression of pro-apoptotic bax

Marissa V. Powers, Melanie Valenti, Susana Miranda, Alison Maloney, Suzanne A. Eccles, George Thomas, Paul A. Clarke, Paul Workman

Research output: Contribution to journalArticlepeer-review

27 Scopus citations

Abstract

Inhibitors of the molecular chaperone heat shock protein 90 (HSP90) are of considerable current interest as targeted cancer therapeutic agents because of the ability to destabilize multiple oncogenic client proteins. Despite their resulting pleiotropic effects on multiple oncogenic pathways and hallmark traits of cancer, resistance to HSP90 inhibitors is possible and their ability to induce apoptosis is less than might be expected. Using an isogenic model for BAX knockout in HCT116 human colon carcinoma cells, we demonstrate the induction of BAX-dependent apoptosis at pharmacologically relevant concentrations of the HSP90 inhibitor 17-AAG both in vitro and in tumor xenografts in vivo. Removal of BAX expression by homologous recombination reduces apoptosis in vitro and in vivo but allows a lower level of cell death via a predominantly necrotic mechanism. Despite reducing apoptosis, the loss of BAX does not alter the overall sensitivity to 17-AAG in vitro or in vivo. The results indicate that 17-AAG acts predominantly to cause a cytostatic antiproliferative effect rather than cell death and further suggest that BAX status may not alter the overall clinical response to HSP90 inhibitors. Other agents may be required in combination to enhance tumor-selective killing by these promising drugs. In addition, there are implications for the use of apoptotic endpoints in the assessment of the activity of molecularly targeted agents.

Original languageEnglish (US)
Pages (from-to)1963-1975
Number of pages13
JournalOncotarget
Volume4
Issue number11
DOIs
StatePublished - Nov 2013

Keywords

  • 17-AAG
  • Apoptosis
  • BAX
  • Colon cancer
  • HSP90

ASJC Scopus subject areas

  • Oncology

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