Induction of NEDD8-conjugating enzyme E2 UBE2F by platinum protects lung cancer cells from apoptosis and confers to platinum-insensitivity.
Induction of NEDD8-conjugating enzyme E2 UBE2F by platinum protects lung cancer cells from apoptosis and confers to platinum-insensitivity.
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铂诱导 NEDD8 结合酶 E2 UBE2F 可保护肺癌细胞免于凋亡并赋予铂不敏感性
DOI：
10.1038/s41419-020-03184-4
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发表时间：
2020-11-12
影响因子：
9
通讯作者：
Jia L
中科院分区：
文献类型：
--
作者：
Zhou L;Zhu J;Chen W;Jiang Y;Hu T;Wang Y;Ye X;Zhan M;Ji C;Xu Z;Wang X;Gu Y;Jia L
铂类药物是治疗非小细胞肺癌和腺癌的一线化疗药物。不幸的是，铂类耐药导致复发和治疗失败，使铂类增敏策略的发展具有重要的临床意义。在这里，我们报告了NEDD 8结合酶UBE 2F的上调是肺癌细胞逃避铂诱导的细胞凋亡的重要途径，这导致对铂类化疗不敏感。从机制上讲，铂处理损害了蛋白酶体介导的UBE 2F降解的复合物形成，这通过UBE 2F与环盒蛋白1（RBX 1）（Cullin-Ring E3连接酶（CRL）的重要组分）之间的较弱缔合得到证明，从而导致UBE 2F蓄积。累积的UBE 2F促进Cullin 5的neddylation水平和活性，与促凋亡蛋白NOXA（Cullin-Ring E3连接酶5（CRL 5）的众所周知的底物）的较低表达雅阁。此外，UBE 2F的敲除通过提高NOXA的蛋白水平并随后促进细胞凋亡而显著地使肺癌细胞对铂治疗敏感。我们的观察揭示了一个以前未知的调节机制，UBE 2F稳定铂化疗，并建议UBE 2F可能是一个新的治疗靶点敏感肺癌细胞铂为基础的化疗。
Platinum is a widely used first-line chemotherapy in treating non-small cell lung cancer of adenocarcinoma. Unfortunately, platinum resistance leads to relapse and therapeutic failure, enabling the development of platinum-sensitization strategies to be of great clinical significance. Here, we report that the upregulation of the NEDD8-conjugating enzyme UBE2F is an important way for lung cancer cells to escape platinum-induced cell apoptosis, which confers to insensitivity to platinum-based chemotherapy. Mechanistically, platinum treatment impairs the complex formation for proteasome-mediated UBE2F degradation, evidenced by the weaker association between UBE2F and Ring-box protein 1 (RBX1), an essential component of Cullin-Ring E3 ligases (CRLs), thus leading to the accumulation of UBE2F. The accumulated UBE2F promotes the neddylation levels and activity of Cullin5, in accord with the lower expression of pro-apoptotic protein NOXA, a well-known substrate of Cullin-Ring E3 ligase 5 (CRL5). Additionally, knockout of UBE2F significantly sensitizes lung cancer cells to platinum treatment by enhancing the protein levels of NOXA and subsequently promoting cell apoptosis. Our observations uncover a previously unknown regulatory mechanism of UBE2F stability upon platinum chemotherapy and suggest that UBE2F might be a novel therapy target for sensitizing lung cancer cells to platinum-based chemotherapy.
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蛋白质 neddylation 及其在人类癌症中的改变用于靶向治疗。
影响因子：
4.8
作者：
Zhou L;Zhang W;Sun Y;Jia L
通讯作者：
Jia L
靶向蛋白质 Neddylation 用于癌症治疗
DOI：
10.1007/978-981-15-1025-0_18
发表时间：
2020-01-01
期刊：
CULLIN-RING LIGASES AND PROTEIN NEDDYLATION: BIOLOGY AND THERAPEUTICS
影响因子：
--
作者：
Zhou, Lisha;Jia, Lijun
通讯作者：
Jia, Lijun
影响因子：
16
作者：
Huang, DT;Paydar, A;Schulman, BA
通讯作者：
Schulman, BA
影响因子：
8.8
作者：
Brown JS;Lukashchuk N;Sczaniecka-Clift M;Britton S;le Sage C;Calsou P;Beli P;Galanty Y;Jackson SP
通讯作者：
Jackson SP
通过 NF-kappa B-CCL2 信号传导提高 neddylation 通路促进肺癌中肿瘤相关巨噬细胞浸润
影响因子：
8
作者：
Zhou, Lisha;Jiang, Yanyu;Jia, Lijun
通讯作者：
Jia, Lijun