Cholinergic signaling via muscarinic M1 receptor confers resistance to docetaxel in prostate cancer

Jing Wang, Jing Wei, Tianjie Pu, Alan Zeng, Varsha Karthikeyan, Baron Bechtold, Karen Vo, Jingrui Chen, Tzu Ping Lin, Amy P. Chang, Eva Corey, Martin Puhr, Helmut Klocker, Zoran Culig, Tyler Bland*, Boyang Jason Wu*

*此作品的通信作者

研究成果: Article同行評審

5 引文 斯高帕斯(Scopus)

摘要

Docetaxel is the most commonly used chemotherapy for advanced prostate cancer (PC), including castration-resistant disease (CRPC), but the eventual development of docetaxel resistance constitutes a major clinical challenge. Here, we demonstrate activation of the cholinergic muscarinic M1 receptor (CHRM1) in CRPC cells upon acquiring resistance to docetaxel, which is manifested in tumor tissues from PC patients post- vs. pre-docetaxel. Genetic and pharmacological inactivation of CHRM1 restores the efficacy of docetaxel in resistant cells. Mechanistically, CHRM1, via its first and third extracellular loops, interacts with the SEMA domain of cMET and forms a heteroreceptor complex with cMET, stimulating a downstream mitogen-activated protein polykinase program to confer docetaxel resistance. Dicyclomine, a clinically available CHRM1-selective antagonist, reverts resistance and restricts the growth of multiple docetaxel-resistant CRPC cell lines and patient-derived xenografts. Our study reveals a CHRM1-dictated mechanism for docetaxel resistance and identifies a CHRM1-targeted combinatorial strategy for overcoming docetaxel resistance in PC.

原文English
文章編號101388
期刊Cell Reports Medicine
5
發行號2
DOIs
出版狀態Published - 20 2月 2024

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