Bortezomib-induced heat shock response protects multiple myeloma cells and is activated by heat shock factor 1 serine 326 phosphorylation.

Shardule P Shah,Lawrence H Boise,Sagar Lonial,Nizar J Bahlis,David L Jaye,Ajay K Nooka

doi:10.18632/oncotarget.10847

Abstract

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.

Highlights

In 2016, an estimated 30,330 people will be diagnosed with multiple myeloma, a plasma cell malignancy that historically affects older individuals [1]
RNA was extracted from isolated CD138+ cells from four different myeloma patients following bortezomib treatment (Figure 1A). cDNA was probed for changes in heat shock proteins (HSPs) and Heat Shock Factor 1 (HSF1) gene expression using qPCR
Bortezomib has been a mainstay of myeloma therapy since its Food and Drug Administration (FDA) approval in 2003 and is commonly used in combination with cyclophosphamide, melphalan, prednisone, IMiDs, and dexamethasone [39]

Summary

Introduction

In 2016, an estimated 30,330 people will be diagnosed with multiple myeloma, a plasma cell malignancy that historically affects older individuals [1]. Myeloma cells retain many of the same functions as their normal counterpart, long-lived bone marrow plasma cells, including immunoglobulin secretion [2]. Because plasma cells are constitutive immunoglobulin producers, they are dependent on the proteasome for quality control and survival, and myeloma cells retain this dependence [2, 3]. Bortezomib has been a mainstay of myeloma therapy since its Food and Drug Administration (FDA) approval for refractory myeloma in 2003 [4]. Two additional proteasome inhibitors have recently been FDA-approved for myeloma therapy, highlighting the importance of this class of agents for the treatment of this disease [6,7,8,9,10,11,12]

Methods

Results

Conclusion