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Bortezomib-induced heat shock response protects multiple myeloma cells and is activated by heat shock factor 1 serine

Shardule P Shah1, Ajay K Nooka1, David L Jaye1,2

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

Oncotarget
|August 4, 2016
PubMed

Insights

Targeting Heat Shock Factor 1 (HSF1) enhances bortezomib efficacy in multiple myeloma by inhibiting the heat shock response. Silencing HSF1, not individual heat shock proteins, sensitized cells to bortezomib, revealing a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cellular Stress Response

Background:

  • Proteasome inhibitors like bortezomib are effective in multiple myeloma but induce a cytoprotective heat shock response (HSR).
  • The HSR involves the upregulation of heat shock proteins (HSPs), which can counteract drug-induced stress.

Purpose of the Study:

  • To investigate the role of Heat Shock Factor 1 (HSF1), the master regulator of HSR, in bortezomib resistance.
  • To explore HSF1 activation mechanisms and its potential as a therapeutic target in multiple myeloma.

Main Methods:

  • Silencing of HSF1 and individual HSPs using genetic approaches.
  • Assessment of bortezomib sensitivity in treated cell lines and patient samples.
  • Analysis of HSF1 phosphorylation at serine 326.

Main Results:

  • HSF1 silencing significantly sensitized multiple myeloma cells to bortezomib.
  • Silencing of most individual HSPs, except HSP40β, did not enhance bortezomib sensitivity.
  • Bortezomib treatment induced phosphorylation of HSF1 at serine 326 in cell lines and patient samples.

Conclusions:

  • HSF1, rather than individual HSPs, is a key mediator of the bortezomib-induced HSR in multiple myeloma.
  • Targeting HSF1 activation, specifically phosphorylation at serine 326, offers a promising strategy to overcome bortezomib resistance.
  • Combining HSF1 inhibition with bortezomib may improve therapeutic outcomes in multiple myeloma.
Keywords:
HSF1bortezomibheat shockmyeloma

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