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Hsp90B enhances MAST1-mediated cisplatin resistance by protecting MAST1 from proteosomal degradation

Chaoyun Pan1, Jaemoo Chun1, Dan Li1

  • 1Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory, Emory University School of Medicine, Atlanta, Georgia, USA.

The Journal of Clinical Investigation
|August 27, 2019
PubMed

Insights

Heat shock protein 90 B (hsp90B) stabilizes MAST1, driving cisplatin resistance in cancers. Targeting hsp90B destabilizes MAST1, sensitizing tumors to cisplatin and offering a novel therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Microtubule-associated serine/threonine kinase 1 (MAST1) drives cisplatin resistance in human cancers.
  • The precise molecular mechanisms governing MAST1 levels in resistant tumors remain unclear.

Purpose of the Study:

  • To elucidate the regulatory mechanism of MAST1 in cisplatin-resistant cancers.
  • To identify novel therapeutic targets for overcoming cisplatin resistance.

Main Methods:

  • Proteomics screening to identify MAST1 binding partners.
  • In vitro assays to assess protein stabilization and ubiquitination.
  • In vivo studies using patient-derived xenograft models.

Main Results:

  • Heat shock protein 90 B (hsp90B) was identified as a MAST1 binding partner crucial for its stabilization.
  • Targeting hsp90B led to MAST1 destabilization and sensitized cancer cells to cisplatin.
  • hsp90B interaction inhibited CHIP-mediated ubiquitination and proteasomal degradation of MAST1.
  • The hsp90B-MAST1-CHIP axis was clinically validated in cancer patients.
  • Combined hsp90 and MAST1 inhibition enhanced cisplatin efficacy in a xenograft model.

Conclusions:

  • The hsp90B-MAST1-CHIP signaling axis is a key regulator of MAST1 stability and cisplatin response.
  • Inhibiting hsp90B or combining hsp90 and MAST1 inhibitors presents a promising strategy to overcome cisplatin resistance.
Keywords:
Head and neck cancerOncologyProtein kinasesTherapeuticsUbiquitin-proteosome system

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