Details

Autor(en) / Beteiligte

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

Titel

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

Ist Teil von

• Cell reports. Medicine, 2024-02, Vol.5 (2), p.101388-101388, Article 101388

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2024

Link zum Volltext

Quelle

Free E-Journal (出版社公開部分のみ）

Beschreibungen/Notizen

• 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. [Display omitted] •CHRM1 is activated in CRPC cells upon acquisition of resistance to docetaxel•CHRM1 is elevated in tumor tissues from prostate cancer patients after chemotherapy•CHRM1 interacts with cMET to induce a polykinase program for docetaxel resistance•CHRM1 inhibitor dicyclomine treatment overcomes docetaxel resistance Wang et al. identify CHRM1 as a regulator of docetaxel resistance and aggressiveness in prostate cancer. CHRM1 is induced in prostate cancer cells and patient samples after chemotherapy. CHRM1 interacts with cMET to activate a downstream MAPK polykinase program. Inhibition of CHRM1 restores docetaxel responsiveness.