Cholesterol Triggers Nuclear Co-Association of Androgen Receptor, p160 Steroid Coactivators, and p300/CBP-Associated Factor Leading to Androgenic Axis Transactivation in Castration-Resistant Prostate Cancer.

Autor:	Pimenta R; Laboratorio de Investigação Médica 55 (LIM55), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil, ruanpimenta22@gmail.com.; Instituto D'OR de Pesquisa e Ensino, São Paulo, Brazil., Camargo JA; Laboratorio de Investigação Médica 55 (LIM55), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil., Candido P; Laboratorio de Investigação Médica 55 (LIM55), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil., Ghazarian V; Laboratorio de Investigação Médica 55 (LIM55), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil., Gonçalves GL; Laboratory of Renal Physiology, Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil., Guimarães VR; Laboratorio de Investigação Médica 55 (LIM55), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil., Romão P; Laboratorio de Investigação Médica 55 (LIM55), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil., Chiovatto C; Laboratorio de Investigação Médica 55 (LIM55), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.; Centro Universitário São Camilo, São Paulo, Brazil., Mioshi CM; Laboratorio de Investigação Médica 55 (LIM55), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.; Universidade Federal do ABC, Santo André, Brazil., Dos Santos GA; Laboratorio de Investigação Médica 55 (LIM55), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.; Instituto D'OR de Pesquisa e Ensino, São Paulo, Brazil., Silva IA; Laboratorio de Investigação Médica 55 (LIM55), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil., Birbrair A; Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, Brazil.; Department of Dermatology, University of Wisconsin-Madison, Madison, WI, USA.; Department of Radiology, Columbia University Medical Center, New York, NY, USA., Srougi M; Laboratorio de Investigação Médica 55 (LIM55), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.; Instituto D'OR de Pesquisa e Ensino, São Paulo, Brazil., Nahas WC; Uro-Oncology Group, Urology Department, University of São Paulo Medical School and Institute of Cancer Estate of São Paulo (ICESP), São Paulo, Brazil., Leite KR; Laboratorio de Investigação Médica 55 (LIM55), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil., Viana NI; Laboratorio de Investigação Médica 55 (LIM55), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.; Universidade do Estado de Minas Gerais - UEMG, Passos, Brazil., Reis ST; Laboratorio de Investigação Médica 55 (LIM55), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
Jazyk:	angličtina
Zdroj:	Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology [Cell Physiol Biochem] 2022 Dec 02; Vol. 56 (S4), pp. 1-15.
DOI:	10.33594/000000592
Abstrakt:	Background/aims: Cholesterol modulates intratumoral androgenic signaling in prostate cancer; however, the molecular mechanisms underlying these changes in castration-resistant prostate cancer (CRPC) are not fully elucidated. Herein, we investigated the effect of cholesterol on androgen receptor (AR) coactivators expression and tumorigenesis in vitro and in vivo. Methods: Herein, we monitored the expression of AR coactivators (SRC-1, 2, 3 and PCAF) genes in PC-3 cells exposed to 2µg/mL of cholesterol for 8 hours by qPCR. We also performed cell migration at 0, 8, 24, 48 and 72h and flow cytometry assays (viability, apoptosis, and cell cycle) after a 24h exposure. Immunofluorescence assay was performed to evaluate the protein expression of the AR coactivators. Additionally, in vivo experiments were conducted using 22 male NOD/SCID mice. Mice were fed a standard (Control) or hypercholesterolemic (HCOL) diet for 21 days and then subcutaneously implanted with PC-3 cells. The tumor volume was calculated every two days, and after four weeks, the tumors were resected, weighed, and the serum lipid profile was measured. We also measured the intratumoral lipid profile and AR coactivators gene and protein expression by qPCR and Western Blot, respectively. Intratumor testosterone and dihydrotestosterone (DHT) concentrations were determined using ELISA. Results: Cholesterol up-regulated the gene expression of coactivators SRC-1, SRC-2, SRC-3 and PCAF, increasing AR expression in PC-3 cells. Next, cholesterol-supplemented PC-3 cells exhibited increased cell migration and altered cell cycle phases, leading to changes in proliferation and reduced apoptosis. We found that SRC-1, SRC-2, SRC-3 and PCAF proteins co-localized in the nucleus of cholesterol-supplemented cells and co-associate with AR. In the in vivo model, the hypercholesterolemic (HCOL) group displayed higher serum total and intratumoral cholesterol levels, increased testosterone and dihydrotestosterone concentrations, and up-regulated AR coactivator expression. The tumor volume of the HCOL group was significantly higher than the control group. Conclusion: Our findings revealed that increased nuclear translocation of the coactivators leads to up-regulated AR gene and protein expression, potentially influencing tumor progression. Studies targeting cholesterol-modulated changes in AR coactivator expression may provide insights into the molecular mechanisms associated with the CRPC phenotype. Competing Interests: The authors declare that no conflict of interests exists. (© Copyright by the Author(s). Published by Cell Physiol Biochem Press.)
Databáze:	MEDLINE
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