Cholinergic signaling via muscarinic M1 receptor confers resistance to docetaxel in prostate cancer.
Cell Rep Med
; 5(2): 101388, 2024 Feb 20.
Article
em En
| MEDLINE
| ID: mdl-38262412
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.
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Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Receptor Muscarínico M1
/
Neoplasias de Próstata Resistentes à Castração
Limite:
Humans
/
Male
Idioma:
En
Revista:
Cell Rep Med
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos