Pirh2 mediates the sensitivity of myeloma cells to bortezomib via canonical NF-κB signaling pathway  

作　　者：Li Yang Jing Chen Xiaoyan Han Enfan Zhang Xi Huang Xing Guo Qingxiao Chen Wenjun Wu Gaofeng Zheng Donghua He Yi Zhao Yang Yang Jingsong He Zhen Cai 

机构地区：[1]Multiple Myeloma Treatment Center & Bone Marrow Transplantation Center, The First Affiliated Hospital, College of Medicine,Zhejiang University, Hangzhou 310003, China

出　　处：《Protein & Cell》2018年第9期770-784,共15页蛋白质与细胞（英文版）

摘　　要：Clinical success of the proteasome inhibitor established bortezomib as one of the most effective drugs in treatment of multiple myeloma （MM）. While survival benefit of bortezomib generated new treatment strategies, the primary and secondary resistance of MM cells to bortezomib remains a clinical concern. This study aimed to highlight the role of p53-induced RING-H2 （Pirh2） in the acquisition of bortezomib resistance in MM and to clarify the function and mechanism of action of Pirh2 in MM cell growth and resistance, thereby providing the basis for new therapeutic targets for MM. The proteasome inhibitor bortezomib has been established as one of the most effective drugs for treating MM. We demonstrated that bortezomib resistance in MM cells resulted from a reduction in Pirh2 protein levels. Pirh2 overexpression overcame bortezomib resistance and restored the sensitivity of myeloma cells to bortezomib, while a reduction in Pirh2 levels was correlated with bortezomib resistance. The levels of nuclear factor- kappaB （NF-κB） p65, pp65, plKBa, and IKKa were higher in bortezomib-resistant cells than those in parental cells. Pirh2 overexpression reduced the levels of plKBa and IKKa, while the knockdown of Pirh2 via short hairpin RNAs increased the expression of NF-κB p65, plKBa, and IKKa. Therefore, Pirh2 suppressed the canonical NF- κB signaling pathway by inhibiting the phosphorylation and subsequent degradation of IKBa to overcome acquired bortezomib resistance in MM cells.Clinical success of the proteasome inhibitor established bortezomib as one of the most effective drugs in treatment of multiple myeloma （MM）. While survival benefit of bortezomib generated new treatment strategies, the primary and secondary resistance of MM cells to bortezomib remains a clinical concern. This study aimed to highlight the role of p53-induced RING-H2 （Pirh2） in the acquisition of bortezomib resistance in MM and to clarify the function and mechanism of action of Pirh2 in MM cell growth and resistance, thereby providing the basis for new therapeutic targets for MM. The proteasome inhibitor bortezomib has been established as one of the most effective drugs for treating MM. We demonstrated that bortezomib resistance in MM cells resulted from a reduction in Pirh2 protein levels. Pirh2 overexpression overcame bortezomib resistance and restored the sensitivity of myeloma cells to bortezomib, while a reduction in Pirh2 levels was correlated with bortezomib resistance. The levels of nuclear factor- kappaB （NF-κB） p65, pp65, plKBa, and IKKa were higher in bortezomib-resistant cells than those in parental cells. Pirh2 overexpression reduced the levels of plKBa and IKKa, while the knockdown of Pirh2 via short hairpin RNAs increased the expression of NF-κB p65, plKBa, and IKKa. Therefore, Pirh2 suppressed the canonical NF- κB signaling pathway by inhibiting the phosphorylation and subsequent degradation of IKBa to overcome acquired bortezomib resistance in MM cells.

关 键 词：BORTEZOMIB drug resistance MULTIPLEMYELOMA NF-ΚB Pith2 

分 类 号：Q26[生物学—细胞生物学] Q691