Bortezomib-induced heat shock response protects multiple myeloma cells and is activated by heat shock factor 1 serine 326 phosphorylation
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Shardule P. Shah1, Ajay K. Nooka1, David L. Jaye1,2, Nizar J. Bahlis3, Sagar Lonial1, Lawrence H. Boise1
1Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University and the Emory University School of Medicine, Atlanta, GA, USA
2Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
3Department of Medical Oncology and Hematology, Tom Baker Cancer Center, Calgary, AB, Canada
Lawrence H. Boise, email: firstname.lastname@example.org
Keywords: myeloma, bortezomib, heat shock, HSF1
Received: April 26, 2016 Accepted: June 18, 2016 Published: July 26, 2016
Proteasome inhibitors such as bortezomib are highly active in multiple myeloma by affecting signaling cascades and leading to a toxic buildup of misfolded proteins. Bortezomib-treated cells activate the cytoprotective heat shock response (HSR), including upregulation of heat shock proteins (HSPs). Here we inhibited the bortezomib-induced HSR by silencing its master regulator, Heat Shock Factor 1 (HSF1). HSF1 silencing led to bortezomib sensitization. In contrast, silencing of individual and combination HSPs, except HSP40β, did not result in significant bortezomib sensitization. However, HSP40β did not entirely account for increased bortezomib sensitivity upon HSF1 silencing. To determine the mechanism of HSF1 activation, we assessed phosphorylation and observed bortezomib-inducible phosphorylation in cell lines and patient samples. We determined that this bortezomib-inducible event is phosphorylation at serine 326. Prior clinical use of HSP inhibitors in combination with bortezomib has been disappointing in multiple myeloma therapy. Our results provide a rationale for targeting HSF1 activation in combination with bortezomib to enhance multiple myeloma treatment efficacy.
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