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

doi:10.1016/j.xcrm.2023.101388

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^*

^*Corresponding author for this work

Department of Urology

Research output: Contribution to journal › Article › peer-review

5 Scopus citations

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.

Original language	English
Article number	101388
Journal	Cell Reports Medicine
Volume	5
Issue number	2
DOIs	https://doi.org/10.1016/j.xcrm.2023.101388
State	Published - 20 Feb 2024

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.xcrm.2023.101388

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Wang, J., Wei, J., Pu, T., Zeng, A., Karthikeyan, V., Bechtold, B., Vo, K., Chen, J., Lin, T. P., Chang, A. P., Corey, E., Puhr, M., Klocker, H., Culig, Z., Bland, T., & Wu, B. J. (2024). Cholinergic signaling via muscarinic M1 receptor confers resistance to docetaxel in prostate cancer. Cell Reports Medicine, 5(2), Article 101388. https://doi.org/10.1016/j.xcrm.2023.101388

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title = "Cholinergic signaling via muscarinic M1 receptor confers resistance to docetaxel in prostate cancer",

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",

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

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doi = "10.1016/j.xcrm.2023.101388",

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T1 - Cholinergic signaling via muscarinic M1 receptor confers resistance to docetaxel in prostate cancer

AU - Wang, Jing

AU - Wei, Jing

AU - Pu, Tianjie

AU - Zeng, Alan

AU - Karthikeyan, Varsha

AU - Bechtold, Baron

AU - Vo, Karen

AU - Chen, Jingrui

AU - Lin, Tzu Ping

AU - Chang, Amy P.

AU - Corey, Eva

AU - Puhr, Martin

AU - Klocker, Helmut

AU - Culig, Zoran

AU - Bland, Tyler

AU - Wu, Boyang Jason

PY - 2024/2/20

Y1 - 2024/2/20

N2 - 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.

AB - 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.

KW - CHRM1

KW - MAPK pathway

KW - acetylcholine

KW - cMET

KW - dicyclomine

KW - docetaxel resistance

KW - muscarinic receptor

KW - prostate cancer

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

Abstract

Keywords

UN SDGs

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