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

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

  • Cell Rep Med. 2024 Feb 20;5(2):101388. doi: 10.1016/j.xcrm.2023.101388.
Jing Wang 1 Jing Wei 1 Tianjie Pu 1 Alan Zeng 2 Varsha Karthikeyan 3 Baron Bechtold 1 Karen Vo 4 Jingrui Chen 1 Tzu-Ping Lin 5 Amy P Chang 6 Eva Corey 7 Martin Puhr 8 Helmut Klocker 8 Zoran Culig 8 Tyler Bland 9 Boyang Jason Wu 10
Affiliations

Affiliations

  • 1 Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA.
  • 2 Undergraduate Programs, University of Washington, Seattle, WA, USA.
  • 3 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.
  • 4 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.
  • 5 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.
  • 6 Institute of Microbiology and Immunology, National Yang Ming Chiao Tung University, Taipei, Republic of China.
  • 7 Department of Urology, University of Washington, Seattle, WA, USA.
  • 8 Division of Experimental Urology, Department of Urology, Medical University of Innsbruck, Innsbruck, Austria.
  • 9 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.
  • 10 Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA, USA. Electronic address: boyang.wu@wsu.edu.
Abstract

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.

Keywords

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

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