Introduction: Neuroendocrine transdifferentiation (NED) of prostate cancer (PC) cells is associated with the development of resistance to antiandrogen therapy and poor prognosis in patients with castration-resistant PC (CRPC). Many of the molecular events, involved in NED, appear to be mediated by epigenetic mechanisms. In this study, we evaluated the antitumor activity and epigenetic modulation of 2 epigenetic drugs, such as the demethylating agent 5-aza-2 '-deoxycytidine (AZA) and the methyl donor S-adenosylmethionine (SAM), in 2 human CRPC cell lines with NED (DU-145 and PC-3). Methods: The effects of AZA and SAM on cell viability, cell cycle, apoptosis, migration, and genome-wide DNA methylation profiling have been evaluated. Results: Both drugs showed a prominent antitumor activity in DU-145 and PC-3 cells, through perturbation of cell cycle progression, induction of apoptosis, and inhibition of cell migration. AZA and SAM reversed NED in DU-145 and PC-3, respectively. Moreover, AZA treatment modified DNA methylation pattern in DU-145 cells, sustaining a pervasive hypomethylation of the genome, with a relevant effect on several pathways involved in the regulation of cell proliferation, apoptosis, and cell migration, in particular Wnt/beta-catenin. Conclusions: A relevant antitumor activity of these epigenetic drugs on CRPC cell lines with NED opens a new scenario in the therapy of this lethal variant of PC.

Role of epigenetic therapy in the modulation of tumor growth and migration in human castration-resistant prostate cancer cells with neuroendocrine differentiation / A. Dicitore, M.G. Bacalini, D. Saronni, G. Gaudenzi, M.C. Cantone, G. Gelmini, E.S. Grassi, D. Gentilini, M.O. Borghi, A.M. Di Blasio, L. Persani, P. Garagnani, C. Franceschi, G. Vitale. - In: NEUROENDOCRINOLOGY. - ISSN 0028-3835. - 112:6(2022), pp. 580-594. [10.1159/000518801]

Role of epigenetic therapy in the modulation of tumor growth and migration in human castration-resistant prostate cancer cells with neuroendocrine differentiation

A. Dicitore
Primo
;
D. Saronni;G. Gaudenzi;M.C. Cantone;G. Gelmini;E.S. Grassi;D. Gentilini;M.O. Borghi;L. Persani;G. Vitale
Ultimo
2022

Abstract

Introduction: Neuroendocrine transdifferentiation (NED) of prostate cancer (PC) cells is associated with the development of resistance to antiandrogen therapy and poor prognosis in patients with castration-resistant PC (CRPC). Many of the molecular events, involved in NED, appear to be mediated by epigenetic mechanisms. In this study, we evaluated the antitumor activity and epigenetic modulation of 2 epigenetic drugs, such as the demethylating agent 5-aza-2 '-deoxycytidine (AZA) and the methyl donor S-adenosylmethionine (SAM), in 2 human CRPC cell lines with NED (DU-145 and PC-3). Methods: The effects of AZA and SAM on cell viability, cell cycle, apoptosis, migration, and genome-wide DNA methylation profiling have been evaluated. Results: Both drugs showed a prominent antitumor activity in DU-145 and PC-3 cells, through perturbation of cell cycle progression, induction of apoptosis, and inhibition of cell migration. AZA and SAM reversed NED in DU-145 and PC-3, respectively. Moreover, AZA treatment modified DNA methylation pattern in DU-145 cells, sustaining a pervasive hypomethylation of the genome, with a relevant effect on several pathways involved in the regulation of cell proliferation, apoptosis, and cell migration, in particular Wnt/beta-catenin. Conclusions: A relevant antitumor activity of these epigenetic drugs on CRPC cell lines with NED opens a new scenario in the therapy of this lethal variant of PC.
apoptosis; castration-resistant prostate cancer; DNA methylation; epigenetic drugs; migration
Settore MED/13 - Endocrinologia
2-ago-2021
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/891820
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