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

CHRM1 MAPK pathway acetylcholine cMET dicyclomine docetaxel resistance muscarinic receptor prostate cancer

Journal

Cell reports. Medicine
ISSN: 2666-3791
Titre abrégé: Cell Rep Med
Pays: United States
ID NLM: 101766894

Informations de publication

Date de publication:
17 Jan 2024
Historique:
received: 29 12 2022
revised: 10 11 2023
accepted: 22 12 2023
medline: 24 1 2024
pubmed: 24 1 2024
entrez: 23 1 2024
Statut: aheadofprint

Résumé

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.

Identifiants

DOI: 10.1016/j.xcrm.2023.101388 PMID: 38262412
pubmed: 38262412
pii: S2666-3791(23)00617-1
doi: 10.1016/j.xcrm.2023.101388
pii:
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

101388

Informations de copyright

Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of interests T.B., B.B., K.V., and B.J.W. have a patent pending for using muscarinic acetylcholine receptor inhibitors to treat chemotherapy-resistant cancers. E.C. received sponsored research funding from Sanofi, Gilead, AbbVie, Genentech, Janssen Research, Astra Zeneca, GSK, Bayer Pharmaceuticals, Forma Pharmaceuticals, Foghorn, Kronos, and MacroGenics.

Auteurs

Jing Wang (J)

Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA.

Jing Wei (J)

Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA.

Tianjie Pu (T)

Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA.

Alan Zeng (A)

Undergraduate Programs, University of Washington, Seattle, WA, USA.

Varsha Karthikeyan (V)

Summer Undergraduate Research Fellowship Program, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA; Department of Integrative Biology, School of Life Sciences, College of Science, Oregon State University, Corvallis, OR, USA.

Baron Bechtold (B)

Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA.

Karen Vo (K)

Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA; Summer Undergraduate Research Fellowship Program, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA.

Jingrui Chen (J)

Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA.

Tzu-Ping Lin (TP)

Department of Urology, Taipei Veterans General Hospital, Taipei, Taiwan, Republic of China; Department of Urology, School of Medicine and Shu-Tien Urological Research, National Yang Ming Chiao Tung University, Taipei, Republic of China.

Amy P Chang (AP)

Institute of Microbiology and Immunology, National Yang Ming Chiao Tung University, Taipei, Republic of China.

Eva Corey (E)

Department of Urology, University of Washington, Seattle, WA, USA.

Martin Puhr (M)

Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.

Helmut Klocker (H)

Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.

Zoran Culig (Z)

Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.

Tyler Bland (T)

Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA; WWAMI Medical Education Program, University of Idaho, Moscow, ID, USA. Electronic address: tbland@uidaho.edu.

Boyang Jason Wu (BJ)

Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA. Electronic address: boyang.wu@wsu.edu.

Classifications MeSH