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Trpm8 Expression in Human and Mouse Castration Resistant Prostate Adenocarcinoma Paves the Way for the Preclinical Development of TRPM8-Based Targeted Therapies

Metastatic prostate cancer (mPCa) is one of the leading causes of cancer-related mortality in both the US and Europe. Androgen deprivation is the first-line therapy for mPCa; however, resistance to therapy inevitably occurs and the disease progresses to the castration resistant stage, which is uncur...

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Autores principales: Genovesi, Sacha, Moro, Riccardo, Vignoli, Beatrice, De Felice, Dario, Canossa, Marco, Montironi, Rodolfo, Carbone, Francesco Giuseppe, Barbareschi, Mattia, Lunardi, Andrea, Alaimo, Alessandro
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8961668/
https://www.ncbi.nlm.nih.gov/pubmed/35204694
http://dx.doi.org/10.3390/biom12020193
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author Genovesi, Sacha
Moro, Riccardo
Vignoli, Beatrice
De Felice, Dario
Canossa, Marco
Montironi, Rodolfo
Carbone, Francesco Giuseppe
Barbareschi, Mattia
Lunardi, Andrea
Alaimo, Alessandro
author_facet Genovesi, Sacha
Moro, Riccardo
Vignoli, Beatrice
De Felice, Dario
Canossa, Marco
Montironi, Rodolfo
Carbone, Francesco Giuseppe
Barbareschi, Mattia
Lunardi, Andrea
Alaimo, Alessandro
author_sort Genovesi, Sacha
collection PubMed
description Metastatic prostate cancer (mPCa) is one of the leading causes of cancer-related mortality in both the US and Europe. Androgen deprivation is the first-line therapy for mPCa; however, resistance to therapy inevitably occurs and the disease progresses to the castration resistant stage, which is uncurable. A definition of novel targeted therapies is necessary for the establishment of innovative and more effective protocols of personalized oncology. We employed genetically engineered mouse models of PCa and human samples to characterize the expression of the TRPM8 cation channel in both hormone naïve and castration resistant tumors. We show that Trpm8 expression marks both indolent (Pten-null) and aggressive (Pten/Trp53 double-null and TRAMP) mouse prostate adenocarcinomas. Importantly, both mouse and human castration-resistant PCa preserve TRPM8 protein expression. Finally, we tested the effect of TRPM8 agonist D-3263 administration in combination with enzalutamide or docetaxel on the viability of aggressive mouse PCa cell lines. Our data demonstrate that D-3263 substantially enhances the pro-apoptotic activity of enzalutamide and docetaxel in TRAMP-C1 e TRAMP-C2 PCa cell lines. To conclude, this study provides the basis for pre-clinical in vivo testing of TRPM8 targeting as a novel strategy to implement the efficacy of standard-of-care treatments for advanced PCa.
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spelling pubmed-89616682022-03-30 Trpm8 Expression in Human and Mouse Castration Resistant Prostate Adenocarcinoma Paves the Way for the Preclinical Development of TRPM8-Based Targeted Therapies Genovesi, Sacha Moro, Riccardo Vignoli, Beatrice De Felice, Dario Canossa, Marco Montironi, Rodolfo Carbone, Francesco Giuseppe Barbareschi, Mattia Lunardi, Andrea Alaimo, Alessandro Biomolecules Article Metastatic prostate cancer (mPCa) is one of the leading causes of cancer-related mortality in both the US and Europe. Androgen deprivation is the first-line therapy for mPCa; however, resistance to therapy inevitably occurs and the disease progresses to the castration resistant stage, which is uncurable. A definition of novel targeted therapies is necessary for the establishment of innovative and more effective protocols of personalized oncology. We employed genetically engineered mouse models of PCa and human samples to characterize the expression of the TRPM8 cation channel in both hormone naïve and castration resistant tumors. We show that Trpm8 expression marks both indolent (Pten-null) and aggressive (Pten/Trp53 double-null and TRAMP) mouse prostate adenocarcinomas. Importantly, both mouse and human castration-resistant PCa preserve TRPM8 protein expression. Finally, we tested the effect of TRPM8 agonist D-3263 administration in combination with enzalutamide or docetaxel on the viability of aggressive mouse PCa cell lines. Our data demonstrate that D-3263 substantially enhances the pro-apoptotic activity of enzalutamide and docetaxel in TRAMP-C1 e TRAMP-C2 PCa cell lines. To conclude, this study provides the basis for pre-clinical in vivo testing of TRPM8 targeting as a novel strategy to implement the efficacy of standard-of-care treatments for advanced PCa. MDPI 2022-01-23 /pmc/articles/PMC8961668/ /pubmed/35204694 http://dx.doi.org/10.3390/biom12020193 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Genovesi, Sacha
Moro, Riccardo
Vignoli, Beatrice
De Felice, Dario
Canossa, Marco
Montironi, Rodolfo
Carbone, Francesco Giuseppe
Barbareschi, Mattia
Lunardi, Andrea
Alaimo, Alessandro
Trpm8 Expression in Human and Mouse Castration Resistant Prostate Adenocarcinoma Paves the Way for the Preclinical Development of TRPM8-Based Targeted Therapies
title Trpm8 Expression in Human and Mouse Castration Resistant Prostate Adenocarcinoma Paves the Way for the Preclinical Development of TRPM8-Based Targeted Therapies
title_full Trpm8 Expression in Human and Mouse Castration Resistant Prostate Adenocarcinoma Paves the Way for the Preclinical Development of TRPM8-Based Targeted Therapies
title_fullStr Trpm8 Expression in Human and Mouse Castration Resistant Prostate Adenocarcinoma Paves the Way for the Preclinical Development of TRPM8-Based Targeted Therapies
title_full_unstemmed Trpm8 Expression in Human and Mouse Castration Resistant Prostate Adenocarcinoma Paves the Way for the Preclinical Development of TRPM8-Based Targeted Therapies
title_short Trpm8 Expression in Human and Mouse Castration Resistant Prostate Adenocarcinoma Paves the Way for the Preclinical Development of TRPM8-Based Targeted Therapies
title_sort trpm8 expression in human and mouse castration resistant prostate adenocarcinoma paves the way for the preclinical development of trpm8-based targeted therapies
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8961668/
https://www.ncbi.nlm.nih.gov/pubmed/35204694
http://dx.doi.org/10.3390/biom12020193
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