Targeting the up-regulated CNOT3 reverses therapeutic resistance and metastatic progression of EGFR-mutant non-small cell lung cancer.
Targeting the up-regulated CNOT3 reverses therapeutic resistance and metastatic progression of EGFR-mutant non-small cell lung cancer.
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靶向上调的CNOT3逆转了EGFR突变非小细胞肺癌的治疗性耐药性和转移性进展。
DOI：
10.1038/s41420-023-01701-w
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发表时间：
2023-11-02
影响因子：
7
通讯作者：
Jiang, Jian-Li
中科院分区：
文献类型：
--
作者：
Jing, Lin;Zhai, Meng-En;Qian, Mei-Rui;Li, Yi-Ming;Han, Ming-Wei;Wang, Kun;Huang, Wan;Nan, Gang;Jiang, Jian-Li
肺癌是全球癌症相关死亡的主要原因。hocT 3是CCR 4-NOT复合物的一个亚基，最近被认为在肺癌中过表达，并参与肿瘤的恶性程度。然而，其确切作用和基本机制仍有待充分揭示。在本研究中，我们发现肺癌细胞中hocT 3的表达可以通过EGFR信号通路来调节，EGFR下游的转录因子c-Jun转录调节其表达。有趣的是，hocT 3可以通过调节其翻译来反向调节c-Jun的表达。因此，c-Jun和hocT 3之间存在反馈回路。EGFR阻断后hocT 3减少促进药物诱导的细胞死亡，同时通过影响TSC 1/mTOR轴抑制细胞增殖。然而，在吉非替尼耐药细胞中观察到hocT 3表达的进一步上调，这降低了吉非替尼的敏感性。从机制上讲，hocT 3的升高是由HER 2/c-Jun信号传导的旁路激活诱导的。在体外和体内消耗hocT 3使耐药细胞对吉非替尼治疗敏感并抑制转移进展。这些结果为hocT 3在肺癌恶性肿瘤中的作用提供了新的见解，并为开发治疗策略以解决对EGFR-TKI的获得性耐药提供了理论基础。
Lung cancer is the leading cause of cancer-related mortality worldwide. CNOT3, a subunit of the CCR4-NOT complex, has recently been suggested to be overexpressed in lung cancer and involved in tumor malignancy. However, its precise role and the underlying mechanisms still need to be fully revealed. In the present study, we found in lung cancer cells the expression of CNOT3 could be regulated by EGFR signaling pathway and c-Jun, a transcription factor downstream of EGFR, transcriptionally regulated its expression. Interestingly, CNOT3 could inversely regulate the expression of c-Jun via modulating its translation. Thus, a feedback loop existed between c-Jun and CNOT3. CNOT3 reduction post EGFR blockade facilitated the drug-induced cell death, and simultaneously inhibited cell proliferation via impacting TSC1/mTOR axis. Whereas, further up-regulation of the CNOT3 expression was observed in gefitinib-resistant cells, which dampened gefitinib sensitivity. Mechanically, the elevation of CNOT3 was induced by the bypass activation of HER2/c-Jun signaling. Depleting CNOT3 in vitro and in vivo sensitized the drug-resistant cells to gefitinib treatment and inhibited metastatic progression. These results give novel insights into the role of CNOT3 in lung cancer malignancy and provide a theoretical basis for the development of therapeutic strategies to solve acquired resistance to EGFR-TKIs.
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影响因子：
64.5
作者：
Gillette, Michael A.;Satpathy, Shankha;Carr, Steven A.
通讯作者：
Carr, Steven A.
影响因子：
0.9
作者：
Hall, M N
通讯作者：
Hall, M N
影响因子：
7
作者：
Faraji F;Hu Y;Wu G;Goldberger NE;Walker RC;Zhang J;Hunter KW
通讯作者：
Hunter KW
DOI：
10.1126/science.aay6912
发表时间：
2020-04-17
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Buschauer R;Matsuo Y;Sugiyama T;Chen YH;Alhusaini N;Sweet T;Ikeuchi K;Cheng J;Matsuki Y;Nobuta R;Gilmozzi A;Berninghausen O;Tesina P;Becker T;Coller J;Inada T;Beckmann R
通讯作者：
Beckmann R
影响因子：
7.3
作者：
Collart, Martine A.
通讯作者：
Collart, Martine A.