Pirh2 mediates the sensitivity of myeloma cells to bortezomib via canonical NF-κB signaling pathway.
Pirh2 mediates the sensitivity of myeloma cells to bortezomib via canonical NF-κB signaling pathway.
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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
DOI：
10.1007/s13238-017-0500-9
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发表时间：
2018-09
期刊：
影响因子：
21.1
通讯作者：
Cai Z
中科院分区：
文献类型：
--
作者：
Yang L;Chen J;Han X;Zhang E;Huang X;Guo X;Chen Q;Wu W;Zheng G;He D;Zhao Y;Yang Y;He J;Cai Z
蛋白酶体抑制剂的临床成功使Bortezomib成为治疗多发性骨髓瘤(MM)最有效的药物之一。虽然Bortezomib的生存优势产生了新的治疗策略，但MM细胞对Bortezomib的原发和继发耐药仍然是临床关注的问题。本研究旨在阐明P53诱导的环-H2(Pirh2)在MM细胞获得Bortezomib耐药中的作用，阐明Pirh2在MM细胞生长和耐药中的作用及机制，从而为MM新的治疗靶点提供依据。蛋白酶体抑制剂Bortezomib已被确定为治疗MM的最有效药物之一。Pirh2的表达克服了Bortezomib耐药，并恢复了骨髓瘤细胞对Bortezomib的敏感性，而Pirh2水平的降低与Bortezomib耐药相关。耐药细胞中核转录因子-kappaB(NF-κB)p65、pp65、pIKBA和IKKA的表达水平均高于亲本细胞。Pirh2过表达降低了pIKBA和IKA的表达水平，而通过短发夹状RNA敲除Pirh2则增加了NF-κB p65、pIKBA和IKKA的表达。因此，Pirh2通过抑制κ的磷酸化和随后的降解来抑制典型的NF-IKB信号通路，从而克服MM细胞对Bortezomib的获得性耐药。
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.
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影响因子：
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作者：
Lub S;Maes K;Menu E;De Bruyne E;Vanderkerken K;Van Valckenborgh E
通讯作者：
Van Valckenborgh E
DOI：
10.1158/1078-0432.ccr-09-1071
发表时间：
2009-12-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Ooi MG;Hayden PJ;Kotoula V;McMillin DW;Charalambous E;Daskalaki E;Raje NS;Munshi NC;Chauhan D;Hideshima T;Buon L;Clynes M;O'Gorman P;Richardson PG;Mitsiades CS;Anderson KC;Mitsiades N
通讯作者：
Mitsiades N
影响因子：
11.4
作者：
Malek E;Abdel-Malek MA;Jagannathan S;Vad N;Karns R;Jegga AG;Broyl A;van Duin M;Sonneveld P;Cottini F;Anderson KC;Driscoll JJ
通讯作者：
Driscoll JJ
影响因子：
3
作者：
Masumoto, Kazuma;Kitagawa, Masatoshi
通讯作者：
Kitagawa, Masatoshi
影响因子：
3.7
作者：
Brinkmann K;Schell M;Hoppe T;Kashkar H
通讯作者：
Kashkar H