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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.
Pimenta, Ruan; Camargo, Juliana A; Candido, Patrícia; Ghazarian, Vitória; Gonçalves, Guilherme L; Guimarães, Vanessa R; Romão, Poliana; Chiovatto, Caroline; Mioshi, Carolina M; Dos Santos, Gabriel A; Silva, Iran A; Birbrair, Alexander; Srougi, Miguel; Nahas, William C; Leite, Kátia R; Viana, Nayara I; Reis, Sabrina T.
Afiliación
  • 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.
  • Camargo JA; Instituto D'OR de Pesquisa e Ensino, 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; Laboratorio de Investigação Médica 55 (LIM55), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
  • Guimarães VR; Laboratory of Renal Physiology, Department of Physiology and Biophysics, Institute of Biomedical Sciences, University of 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.
  • Mioshi CM; Laboratorio de Investigação Médica 55 (LIM55), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
  • Dos Santos GA; Centro Universitário São Camilo, 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; Universidade Federal do ABC, Santo André, Brazil.
  • Srougi M; Laboratorio de Investigação Médica 55 (LIM55), Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil.
  • Nahas WC; Instituto D'OR de Pesquisa e Ensino, 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; Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, Brazil.
  • Reis ST; Department of Dermatology, University of Wisconsin-Madison, Madison, WI, USA.
Cell Physiol Biochem ; 56(S4): 1-15, 2022 Dec 02.
Article en En | MEDLINE | ID: mdl-36458578
ABSTRACT
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-3and 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.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Androgénicos / Neoplasias de la Próstata Resistentes a la Castración Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals / Humans / Male Idioma: En Revista: Cell Physiol Biochem Asunto de la revista: BIOQUIMICA / FARMACOLOGIA Año: 2022 Tipo del documento: Article

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Receptores Androgénicos / Neoplasias de la Próstata Resistentes a la Castración Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Animals / Humans / Male Idioma: En Revista: Cell Physiol Biochem Asunto de la revista: BIOQUIMICA / FARMACOLOGIA Año: 2022 Tipo del documento: Article
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