Shah Shardule P, Nooka Ajay K, Jaye David L, Bahlis Nizar J, Lonial Sagar, Boise Lawrence H
Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University and the Emory University School of Medicine, Atlanta, GA, USA.
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA.
Oncotarget. 2016 Sep 13;7(37):59727-59741. doi: 10.18632/oncotarget.10847.
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.
像硼替佐米这样的蛋白酶体抑制剂通过影响信号级联反应并导致错误折叠蛋白的毒性积累，在多发性骨髓瘤中具有高度活性。硼替佐米处理的细胞会激活细胞保护热休克反应（HSR），包括热休克蛋白（HSPs）的上调。在这里，我们通过沉默其主要调节因子热休克因子1（HSF1）来抑制硼替佐米诱导的HSR。HSF1沉默导致硼替佐米致敏。相比之下，除HSP40β外，单个和组合HSPs的沉默均未导致显著的硼替佐米致敏。然而，HSF1沉默后硼替佐米敏感性增加并不能完全由HSP40β来解释。为了确定HSF1激活的机制，我们评估了磷酸化，并在细胞系和患者样本中观察到硼替佐米诱导的磷酸化。我们确定这种硼替佐米诱导的事件是丝氨酸326处的磷酸化。先前在多发性骨髓瘤治疗中联合使用HSP抑制剂和硼替佐米的临床效果并不理想。我们的结果为联合硼替佐米靶向HSF1激活以提高多发性骨髓瘤治疗疗效提供了理论依据。
