Biochemical characterization of nuclear receptors for vitamin d-3 and glucocorticoids in prostate stroma cell microenvironment
| Autor: | Diego F. Pantoja, Sergio A. Onate, Heribelt Tovar, Alejandro A. Hidalgo, Donald L. Trump, Candace S. Johnson, Alejandro Godoy, Roberto Paredes, Viviana P. Montecinos, Eileen M. McNerney |
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| Jazyk: | angličtina |
| Rok vydání: | 2011 |
| Předmět: |
Male
Stromal cell Biophysics Biology Biochemistry Calcitriol receptor Prostate cancer Glucocorticoid receptor Nuclear Receptor Coactivator 1 Receptors Glucocorticoid medicine Transcriptional regulation Tumor Cells Cultured Tumor Microenvironment Humans Receptor Molecular Biology Transcription factor Cell Nucleus Prostatic Neoplasms Cell Biology medicine.disease Molecular biology Gene Expression Regulation Neoplastic Nuclear receptor Cancer research Receptors Calcitriol Stromal Cells |
| Zdroj: | BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Artículos CONICYT CONICYT Chile instacron:CONICYT |
| Popis: | The disruption of stromal cell signals in prostate tissue microenvironment influences the development of prostate cancer to androgen independence. 1α,25-Dihydroxyvitamin D(3) (1,25D(3)) and glucocorticoids, either alone or in combination, have been investigated as alternatives for the treatment of advanced prostate cancers that fails androgen therapies. The effects of glucocorticoids are mediated by the intracellular glucocorticoid receptor (GR). Similarly, the effect of 1,25D(3) is mediated by the 1,25D(3) nuclear receptor (VDR). In this study, fibroblasts from benign- (BAS) and carcinoma-associated stroma (CAS) were isolated from human prostates to characterize VDR and GR function as transcription factors in prostate stroma. The VDR-mediated transcriptional activity assessed using the CYP24-luciferase reporter was limited to 3-fold induction by 1,25D(3) in 9 out of 13 CAS (70%), as compared to >10-fold induction in the BAS clinical sample pair. Expression of His-tagged VDR (Ad-his-VDR) failed to recover the low transcriptional activity of the luciferase reporter in 7 out of 9 CAS. Interestingly, expression of Ad-his-VDR successfully recovered receptor-mediated induction in 2 out of the 9 CAS analyzed, suggesting that changes in the receptor protein itself was responsible for decreased response and resistance to 1,25D(3) action. Conversely, VDR-mediated transcriptional activity was more efficient in 4 out of 13 CAS (30%), as compared to the BAS sample pair. Consistent with the reduced response to 1,25D(3) observed in CAS, chromatin immunoprecipitation (ChIP) assays indicated decreased recruitment of coactivators SRC-1/CBP, without major changes in the recruitment of VDR to the CYP24 promoter. In addition, we observed that GR-mediated transcriptional activity was also altered in CAS, as compared to BAS. Disruption of coactivators SRC-1/CBP recruitment may promote hormone resistance in CaP, and highlights the relevance of molecular diagnosis and drug design in tumor cell microenvironment. |
| Databáze: | OpenAIRE |
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