CK1δ stimulates ubiquitination-dependent proteasomal degradation of ATF4 to promote chemoresistance in gastric Cancer.
CK1δ stimulates ubiquitination-dependent proteasomal degradation of ATF4 to promote chemoresistance in gastric Cancer.
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DOI：
10.1002/ctm2.587
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发表时间：
2021-10
影响因子：
10.6
通讯作者：
Jin H
中科院分区：
文献类型：
--
作者：
Feng L;Li M;Hu X;Li Y;Zhu L;Chen M;Wei Q;Xu W;Zhou Q;Wang W;Chen D;Wang X;Jin H
化疗耐药性仍然是癌症治疗成功的主要障碍，特别是对于晚期癌症。它过去被认为是由基因变化引起的稳定结果。然而，最近的研究表明，在非遗传性改变的参与下，化学抗性也可能是不稳定和可逆的。在本研究中，我们发现转录激活因子4（ATF 4）在化疗耐药的胃癌细胞中表达下调。ATF 4的过表达通过激活CHOP转录来逆转化疗耐药性，从而增强药物诱导的细胞凋亡，反之亦然。此外，酪蛋白激酶1 δ（CK 1 δ）被鉴定为负责ATF 4-S219磷酸化的激酶，其触发βTrCP-介导的ATF 4多聚泛素化，从而促进其随后的蛋白酶体降解。有趣的是，药物戒断逐渐恢复化疗敏感性以及在化疗耐药细胞中的ATF 4表达，突出了动态耐药性对ATF 4蛋白表达的依赖性。与这些发现一致，通过CK 1 δ或蛋白酶体抑制剂抑制ATF 4蛋白降解克服了体外和体内的化学抗性。总之，这些结果表明，CK 1 δ刺激βTrCP依赖性ATF 4聚泛素化和随后的蛋白酶体降解，以促进胃癌的化疗耐药性。用硼替佐米（BTZ）（一种抑制蛋白酶体降解的抗癌药物）稳定ATF 4蛋白可能是提高胃癌化疗疗效的合理策略。化疗耐药可能是不稳定的和可逆的。ATF 4蛋白水平与胃癌化疗耐药性呈负相关。CK 1 δ刺激ATF 4多聚泛素化降解是动态化疗耐药性的原因。靶向ATF 4可能是逆转胃癌耐药的合理策略。
Chemoresistance remains a major obstacle to successful cancer therapy, especially for advanced cancers. It used to be recognised as a stable outcome resulting from genetic changes. However, recent studies showed that chemoresistance can also be unstable and reversible with the involvement of non‐genetic alterations. In the present study, we found that activating transcription factor 4 (ATF4) is downregulated in chemoresistant gastric cancer cells. The over‐expression of ATF4 reversed chemoresistance by activating CHOP transcription to enhance drug‐induced apoptosis, and vice versa. Moreover, casein kinase 1 delta (CK1δ) was identified as the kinase responsible for ATF4‐S219 phosphorylation, which triggered βTrCP‐mediated ATF4 polyubiquitination to promote its proteasomal degradation subsequently. Interestingly, drug withdrawal gradually restored chemosensitivity as well as ATF4 expression in chemoresistant cells, highlighting the dependence of dynamic drug resistance on ATF4 protein expression. In line with these findings, the inhibition of ATF4 protein degradation by CK1δ or proteasome inhibitors overcame chemoresistance both in vitro and in vivo. Taken together, these results indicate that CK1δ stimulates βTrCP‐dependent ATF4 polyubiquitination and subsequent proteasomal degradation to promote chemoresistance in gastric cancer. Stabilisation of the ATF4 protein with bortezomib (BTZ), an anticancer drug that inhibits proteasomal degradation, might be a rational strategy to improve chemotherapeutic efficacy in gastric cancer. Chemoresistance could be unstable and reversible. ATF4 protein level is negatively correlated to chemoresistance in gastric cancer. CK1δ stimulates ATF4 poly‐ubiquitinated degradation is responsible for the dynamic chemoresistance. Targeting ATF4 could be a rational strategy to reverse chemoresistance in gastric cancer.
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影响因子：
5.3
作者：
Lassot, I;Ségéral, E;Margottin-Goguet, F
通讯作者：
Margottin-Goguet, F
Neddylation 抑制通过 ATF4-CHOP-DR5 轴激活人食管癌细胞的外源性凋亡途径
影响因子：
11.5
作者：
Chen, Ping;Hu, Tao;Jia, Lijun
通讯作者：
Jia, Lijun
药物补偿和治疗超出进展 - 耐药性的刺激性。
DOI：
10.1038/nrclinonc.2013.158
发表时间：
2013-10
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Kuczynski EA;Sargent DJ;Grothey A;Kerbel RS
通讯作者：
Kerbel RS
影响因子：
2.5
作者：
Rozpedek W;Pytel D;Mucha B;Leszczynska H;Diehl JA;Majsterek I
通讯作者：
Majsterek I
影响因子：
50.3
作者：
Inuzuka H;Tseng A;Gao D;Zhai B;Zhang Q;Shaik S;Wan L;Ang XL;Mock C;Yin H;Stommel JM;Gygi S;Lahav G;Asara J;Xiao ZX;Kaelin WG Jr;Harper JW;Wei W
通讯作者：
Wei W