Resistance to 2-Hydroxy-Flutamide in Prostate Cancer Cells Is Associated with the Downregulation of Phosphatidylcholine Biosynthesis and Epigenetic Modifications
Authors
Mora Rodríguez, José María; Sánchez Gómez, Belén; Sebastián Martín, Alba; Díaz Yuste, Alba; Sánchez Chapado, Manuel Vicente; [et al.]Identifiers
Permanent link (URI): http://hdl.handle.net/10017/60401DOI: 10.3390/ijms242115626
ISSN: 1661-6596
Date
2023-10-26Affiliation
Universidad de Alcalá. Departamento de Cirugía; Universidad de Alcalá. Departamento de Cirugía, Ciencias Médicas y Sociales. Unidad docente Urología; Universidad de Alcalá. Departamento de Biología de Sistemas. Unidad docente Bioquímica y Biología MolecularFunders
Instituto de Salud Carlos II
Fundación Tatiana Pérez de Guzmán el Bueno
Comunidad de Madrid
Bibliographic citation
International Journal of Molecular Sciences, 2023, v. 24, n. 21, p. 15626-
Keywords
LNCaP cells
Antiandrogens
Dormant cells
Flutamide
Phosphatidylcholine metabolism
Resistant prostate cancer
Description / Notes
18 p.
Project
info:eu-repo/grantAgreement/ISCIII//PI2%/01327/ES//
info:eu-repo/grantAgreement/FTPGB//2023-001/ES//
info:eu-repo/grantAgreement/CAM//REACTUE-CM202102/ES//
Document type
info:eu-repo/semantics/article
Version
info:eu-repo/semantics/publishedVersion
Rights
© 2023 by the authors
Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)
Access rights
info:eu-repo/semantics/openAccess
Abstract
In this study, we examined the metabolic adaptations of a chemoresistant prostate cancer cell line in comparison to a sensitive cell line. We utilized prostate cancer LNCaP cells and subjected them to a stepwise increase in the antiandrogen 2-hydroxy-flutamide (FLU) concentration to generate a FLU-resistant cell line (LN-FLU). These LN-FLU cells displayed characteristics of cancer stem cells, exhibited drug resistance, and showed a significantly reduced expression of Cyclin D1, along with the overexpression of p16, pointing to a proliferation arrest. In comparing the cancer stem-like LN-FLU cells to the LNCaP cells, we observed a decrease in the expression of CTP-choline cytidylyl transferase ? (CCT?), as well as a decline in choline kinase, suggesting altogether a downregulation of the phosphatidylcholine biosynthetic pathway. In addition, we found decreased levels of the protein methyl transferase PRMT2 and the upregulation of the histone deacetylase Sirtuin1 (Sirt1). Analysis of the human prostate cancer samples revealed similar results in a population with high expressions of the stem cell markers Oct4 and ABCB1A1. Our findings suggest that the adaptation of prostate cancer cells to antiandrogens could induce reprogramming into stem cells that survive in a low phosphocholine metabolism and cell cycle arrest and display drug resistance.
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resistance_mora_IJMS_2023.pdf | 3.467Mb |
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resistance_mora_IJMS_2023.pdf | 3.467Mb |
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