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Updated: May 8, 2026

Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors
07:57

Malachite Green Assay for the Discovery of Heat-Shock Protein 90 Inhibitors

Published on: January 20, 2023

Hsp90 inhibitors promote p53-dependent apoptosis through PUMA and Bax

Kan He1,2, Xingnan Zheng1,2, Lin Zhang3,2

  • 1Department of Pathology, University of Pittsburgh School of Medicine, 5117 Centre Ave., Pittsburgh, PA 15213, USA.

Molecular Cancer Therapeutics
|August 23, 2013
PubMed

Insights

Hsp90 inhibitors trigger colon cancer cell death by activating the p53/PUMA/Bax pathway, leading to DNA damage and apoptosis. This mechanism is crucial for the therapeutic effects of Hsp90 inhibitors in p53 wild-type cancers.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Cellular Biology

Background:

  • Heat shock protein 90 (Hsp90) is overexpressed in cancer cells, maintaining malignant phenotypes.
  • Hsp90 inhibitors show promise in treating various cancers by degrading client oncoproteins.

Purpose of the Study:

  • To investigate the molecular mechanisms by which Hsp90 inhibitors induce apoptosis in colon cancer cells.
  • To elucidate the role of the p53 pathway in mediating the anti-cancer effects of Hsp90 inhibitors.

Main Methods:

  • Treatment of colon cancer cells with structurally unrelated Hsp90 inhibitors, including 17-allylamino-17-demethoxygeldanamycin (17-AAG).
  • Assessment of DNA damage, apoptosis, mitochondrial dysfunction, and clonogenic survival.
  • Evaluation of the roles of p53, PUMA, and BAX using gene-deficient cells and xenograft models.

Main Results:

  • Hsp90 inhibitors induced DNA damage and apoptosis via p53-dependent PUMA induction, leading to Bax activation and mitochondrial dysfunction.
  • Deficiency in PUMA, BAX, or p53 impaired 17-AAG-induced apoptosis and enhanced cell survival.
  • PUMA mediated the apoptotic and therapeutic responses to 17-AAG and its analog 17-DMAG in vivo.

Conclusions:

  • The p53/PUMA/Bax axis is critical for Hsp90 inhibitor-induced apoptosis in p53 wild-type colon cancer cells.
  • These findings highlight the importance of the p53 pathway in the efficacy of Hsp90 inhibitors and have implications for clinical applications.

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