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纤毛生成相关激酶 1 通过磷酸化 ERK1 促进乳腺癌细胞增殖和化疗耐药性。

Ciliogenesis-associated Kinase 1 Promotes Breast Cancer Cell Proliferation and Chemoresistance via Phosphorylating ERK1.

机构信息

Department of Pathology, School of Basic Medical Science, Southern Medical University, Guangzhou 510515, Guangdong, China.

Department of Oncology, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, China.

出版信息

Int J Biol Sci. 2024 Apr 8;20(7):2403-2421. doi: 10.7150/ijbs.87442. eCollection 2024.

DOI:10.7150/ijbs.87442
PMID:38725848
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11077371/
Abstract

Ciliogenesis-associated kinase 1 (CILK1) plays a key role in the ciliogenesis and ciliopathies. It remains totally unclear whether CILK1 is involved in tumor progression and therapy resistance. Here, we report that the aberrant high-expression of CILK1 in breast cancer is required for tumor cell proliferation and chemoresistance. Two compounds, CILK1-C30 and CILK1-C28, were identified with selective inhibitory effects towards the Tyr-159/Thr-157 dual-phosphorylation of CILK1, pharmacological inhibition of CILK1 significantly suppressed tumor cell proliferation and overcame chemoresistance in multiple experimental models. Large-scale screen of CILK1 substrates confirmed that the kinase directly phosphorylates ERK1, which is responsible for CILK1-mediated oncogenic function. CILK1 is also indicated to be responsible for the chemoresistance of small-cell lung cancer cells. Our data highlight the importance of CILK1 in cancer, implicating that targeting CILK1/ERK1 might offer therapeutic benefit to cancer patients.

摘要

纤毛发生相关激酶 1（CILK1）在纤毛发生和纤毛病中发挥关键作用。目前尚不清楚 CILK1 是否参与肿瘤进展和治疗耐药。在这里，我们报告 CILK1 在乳腺癌中的异常高表达对于肿瘤细胞增殖和化疗耐药性是必需的。鉴定出两种化合物 CILK1-C30 和 CILK1-C28，它们对 CILK1 的 Tyr-159/Thr-157 双磷酸化具有选择性抑制作用，对 CILK1 的药理学抑制显著抑制肿瘤细胞增殖并在多种实验模型中克服化疗耐药性。CILK1 底物的大规模筛选证实该激酶可直接磷酸化 ERK1，ERK1 负责 CILK1 介导的致癌功能。CILK1 也被证明与小细胞肺癌细胞的化疗耐药性有关。我们的数据强调了 CILK1 在癌症中的重要性，提示靶向 CILK1/ERK1 可能为癌症患者带来治疗益处。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bcc/11077371/45d989a79fa3/ijbsv20p2403g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bcc/11077371/a2f174f15d52/ijbsv20p2403g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bcc/11077371/fc7664b93ece/ijbsv20p2403g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bcc/11077371/930742db2c11/ijbsv20p2403g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bcc/11077371/2760d3be296d/ijbsv20p2403g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bcc/11077371/87f36ea86e5e/ijbsv20p2403g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bcc/11077371/85686d99ed56/ijbsv20p2403g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bcc/11077371/45d989a79fa3/ijbsv20p2403g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bcc/11077371/a2f174f15d52/ijbsv20p2403g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bcc/11077371/fc7664b93ece/ijbsv20p2403g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bcc/11077371/930742db2c11/ijbsv20p2403g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bcc/11077371/2760d3be296d/ijbsv20p2403g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bcc/11077371/87f36ea86e5e/ijbsv20p2403g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bcc/11077371/85686d99ed56/ijbsv20p2403g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/5bcc/11077371/45d989a79fa3/ijbsv20p2403g007.jpg

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本文引用的文献

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Small cell lung cancer: a slightly less orphan disease after immunotherapy.
小细胞肺癌：免疫治疗后略为不那么“孤儿”的疾病。
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The MEK/ERK Network as a Therapeutic Target in Human Cancer.MEK/ERK 网络作为人类癌症的治疗靶点。
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