| Texto completo | |
| Autor(es): Mostrar menos - |
Pimenta, Ruan
;
Camargo, Juliana A.
;
Candido, Patricia
;
Ghazarian, Vitoria
;
Goncalves, Guilherme L.
;
Guimaraes, Vanessa R.
;
Romao, Poliana
;
Chiovatto, Caroline
;
Mioshi, Carolina M.
;
dos Santos, Gabriel A.
;
Silva, Iran A.
;
Birbrair, Alexander
;
Srougi, Miguel
;
Nahas, William C.
;
Leite, Katia R.
;
Viana, Nayara I.
;
Reis, Sabrina T.
Número total de Autores: 17
|
| Tipo de documento: | Artigo Científico |
| Fonte: | CELLULAR PHYSIOLOGY AND BIOCHEMISTRY; v. 56, p. 15-pg., 2022-01-01. |
| Resumo | |
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 2 mu g/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. (c) 2022 The Author(s). Published by Cell Physiol Biochem Press GmbH&Co. KG (AU) | |
| Processo FAPESP: | 18/26528-5 - Mecanismos adaptativos da função renal em um modelo de nefrotoxicidade induzido por adriamicina: participação da sirtuína 1 e claudina-1 |
| Beneficiário: | Guilherme Lopes Gonçalves |
| Modalidade de apoio: | Bolsas no Brasil - Doutorado |
| Processo FAPESP: | 18/19906-3 - Edição genômica com CRISPR/Cas9 para avaliação do papel da MMP9 e seu regulador MIR21 no Câncer de Próstata |
| Beneficiário: | Juliana Alves de Camargo |
| Modalidade de apoio: | Bolsas no Brasil - Doutorado |
| Processo FAPESP: | 20/01317-1 - Avaliação do papel dos microRNAs -17-5p e -137 sobre os cofatores do receptor de andrógeno no câncer de próstata resistente à castração: estudo in vitro e in vivo em modelo hipercolesterolêmico |
| Beneficiário: | Sabrina Thalita dos Reis Faria |
| Modalidade de apoio: | Auxílio à Pesquisa - Regular |
| Processo FAPESP: | 21/02341-6 - Estabelecimento do modelo animal de doença de Peyronie induzido por fibrina |
| Beneficiário: | Caroline Brandão Chiovatto |
| Modalidade de apoio: | Bolsas no Brasil - Iniciação Científica |
| Processo FAPESP: | 19/19138-9 - Estudo do efeito do miR-137 sobre linhagem celular de câncer de próstata resistente à castração em ambiente hipercolesterolêmico. |
| Beneficiário: | Vitória Ghazarian Nunes |
| Modalidade de apoio: | Bolsas no Brasil - Iniciação Científica |
| Processo FAPESP: | 19/00156-7 - Estudo in vivo de coativadores e corepressores do receptor de andrógeno no Câncer de Próstata |
| Beneficiário: | Ruan César Aparecido Pimenta |
| Modalidade de apoio: | Bolsas no Brasil - Doutorado |