PIrH2 通过经典 NF-κB 信号通路介导骨髓瘤细胞对硼替佐米的敏感性。

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

机构信息

Multiple Myeloma Treatment Center & Bone Marrow Transplantation Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003, China.

出版信息

Protein Cell. 2018 Sep;9(9):770-784. doi: 10.1007/s13238-017-0500-9. Epub 2018 Feb 13.

DOI:10.1007/s13238-017-0500-9

PMID:29441489

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6107487/

Abstract

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, pIKBa, and IKKa were higher in bortezomib-resistant cells than those in parental cells. Pirh2 overexpression reduced the levels of pIKBa and IKKa, while the knockdown of Pirh2 via short hairpin RNAs increased the expression of NF-κB p65, pIKBa, 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.

摘要

蛋白酶体抑制剂硼替佐米的临床成功确立了其作为多发性骨髓瘤（MM）治疗中最有效的药物之一。虽然硼替佐米的生存获益带来了新的治疗策略，但 MM 细胞对硼替佐米的原发性和继发性耐药仍是临床关注的问题。本研究旨在强调 p53 诱导的环指蛋白 2（Pirh2）在 MM 获得硼替佐米耐药中的作用，并阐明 Pirh2 在 MM 细胞生长和耐药中的功能和作用机制，从而为 MM 的新治疗靶点提供依据。蛋白酶体抑制剂硼替佐米已被确立为治疗 MM 最有效的药物之一。我们证实，MM 细胞中的硼替佐米耐药是由于 Pirh2 蛋白水平降低所致。Pirh2 的过表达克服了硼替佐米耐药，并恢复了骨髓瘤细胞对硼替佐米的敏感性，而 Pirh2 水平的降低与硼替佐米耐药相关。核因子-κB（NF-κB）p65、pp65、pIKBa 和 IKKa 在硼替佐米耐药细胞中的水平高于亲本细胞。Pirh2 的过表达降低了 pIKBa 和 IKKa 的水平，而通过短发夹 RNA 敲低 Pirh2 则增加了 NF-κB p65、pIKBa 和 IKKa 的表达。因此，Pirh2 通过抑制 IKBa 的磷酸化及其随后的降解来抑制经典的 NF-κB 信号通路，从而克服 MM 细胞中获得性硼替佐米耐药。