RESUMO
Prostate cancer is an androgen-dependent disease; metastatic prostate cancer is typically treated by androgen receptor (AR) blockade. Recurrence after androgen ablation and evidence that AR continues to play a role in many prostate cancers has led to an examination of other factors that potentiate AR activity. AR is a ligand-activated transcription factor whose activity is regulated not only by hormone but also by the levels of coactivators recruited by AR to facilitate transcription. We sought to assess the consequences of reducing expression of the transcription intermediary factor 2 (TIF2) coactivator on prostate cancer cell growth and AR action in cell lines to examine TIF2 expression in prostate cancer and to correlate expression with clinical outcome. Depletion of TIF2 reduced expression of AR-induced target genes and slowed proliferation of AR-dependent and AR-independent prostate cancer cells. Remarkably, we found that TIF2 expression is directly repressed by high levels of androgens in multiple AR-expressing cell lines. Expression of a reporter containing 5'-flanking region of the TIF2 was repressed both by androgens and by the antagonist, Casodex. Expression of TIF2 correlates with biochemical (prostate-specific antigen) recurrence (P = 0.0136). In agreement with our in vitro findings, the highest expression of TIF2 was found in patients whose cancer relapsed after androgen ablation therapy, supporting the idea that AR blockade might activate pathways that lead to stimulation of AR-dependent and AR-independent proliferation of prostate epithelium. The elevated expression of TIF2 at low hormone levels likely aids in inducing AR activity under these conditions; treatment with Casodex has the potential to counteract this induction.
Assuntos
Androgênios/farmacologia , Neoplasias Hormônio-Dependentes/patologia , Coativador 2 de Receptor Nuclear/fisiologia , Neoplasias da Próstata/patologia , Linhagem Celular Tumoral , Proliferação de Células , Éxons , Humanos , Imuno-Histoquímica , Íntrons , Masculino , Metribolona/farmacologia , Recidiva Local de Neoplasia , Neoplasias Hormônio-Dependentes/química , Coativador 2 de Receptor Nuclear/análise , Coativador 2 de Receptor Nuclear/genética , Neoplasias da Próstata/química , Receptores Androgênicos/metabolismo , Timidina/metabolismoRESUMO
Prostate cancer is the most common cancer in men in America. Currently, steroid receptor coactivators have been proposed to mediate the development and progression of prostate cancer, at times in a steroid-independent manner. Steroid receptor coactivator-3 (SRC-3, p/CIP, AIB1, ACTR, RAC3, and TRAM-1) is a member of the p160 family of coactivators for nuclear hormone receptors including the androgen receptor. SRC-3 is frequently amplified or overexpressed in a number of cancers. However, the role of SRC-3 in cancer cell proliferation and survival is still poorly understood. In this study, we show that SRC-3 is overexpressed in prostate cancer patients and its overexpression correlates with prostate cancer proliferation and is inversely correlated with apoptosis. Consistent with patient data, we have observed that reduction of SRC-3 expression by small interfering RNA decreases proliferation, delays the G1-S transition, and increases cell apoptosis of different prostate cancer cell lines. Furthermore, with decreased SRC-3 expression, proliferating cell nuclear antigen and Bcl-2 expression, as well as bromodeoxyuridine incorporation in prostate cancer cells are reduced. Finally, knockdown of SRC-3 with inducible short hairpin RNA expression in prostate cancer cells decreased tumor growth in nude mice. Taken together, these findings indicate that SRC-3 is an important regulator of prostate cancer proliferation and survival.
Assuntos
Acetiltransferases/fisiologia , Proteínas Oncogênicas/fisiologia , Neoplasias da Próstata/patologia , Transativadores/fisiologia , Acetiltransferases/biossíntese , Acetiltransferases/genética , Animais , Processos de Crescimento Celular , Linhagem Celular Tumoral , Sobrevivência Celular/fisiologia , Regulação para Baixo , Histona Acetiltransferases , Humanos , Masculino , Camundongos , Camundongos Nus , Coativador 3 de Receptor Nuclear , Proteínas Oncogênicas/biossíntese , Proteínas Oncogênicas/genética , Antígeno Prostático Específico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/fisiologia , RNA Interferente Pequeno/genética , Transativadores/biossíntese , Transativadores/genéticaRESUMO
A considerable body of evidence indicates that alterations of fibroblast growth factors (FGFs) and their receptors contribute to prostate cancer progression. Recently, a new family of regulators of FGF activity has been identified. The Sprouty gene family negatively regulates FGF signaling in a variety of systems and could potentially limit the biological activity of FGFs in prostate cancer. Immunohistochemical analysis of normal and neoplastic prostate tissues using tissue microarrays revealed that Sprouty1 protein is down-regulated in approximately 40% of prostate cancers when compared with matched normal prostate. By quantitative real-time PCR analysis, we found that Sprouty1 mRNA levels were significantly decreased in prostate cancers in vivo in comparison with normal prostate. In prostate cancer cell lines, there is loss of the normal up-regulation of Sprouty1 mRNA and protein in response to FGFs. The decrease in Sprouty1 expression in the human prostate cancer, despite elevated levels of FGF ligands and FGF receptors, implies a loss of an important growth regulatory mechanism in prostate cancers that may potentiate the effects of increased FGF and FGF receptor expression in prostate cancer.
Assuntos
Proteínas de Membrana/biossíntese , Fosfoproteínas/biossíntese , Neoplasias da Próstata/metabolismo , Linhagem Celular Tumoral , Análise Mutacional de DNA , Células Epiteliais/metabolismo , Células Epiteliais/fisiologia , Fator 2 de Crescimento de Fibroblastos/farmacologia , Fatores de Crescimento de Fibroblastos/biossíntese , Fatores de Crescimento de Fibroblastos/fisiologia , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Masculino , Proteínas de Membrana/genética , Fosfoproteínas/genética , Neoplasias da Próstata/genética , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores de Fatores de Crescimento de Fibroblastos/biossíntese , Receptores de Fatores de Crescimento de Fibroblastos/fisiologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transfecção , Regulação para CimaRESUMO
Steroid receptor coactivator-3 (SRC-3)/AIB1 is a member of the p160 nuclear receptor coactivator family involved in development and cell cycle progression. We previously showed that SRC-3/AIB1 is required for prostate cancer cell proliferation and survival. Here, we reported that the elevated SRC-3/AIB1 expression is significantly correlated with human prostate cancer seminal vesicle invasion and lymph node metastasis. Furthermore, SRC-3/AIB1 is associated with increased prostate cancer cell migration and invasion. SRC-3/AIB1 is required for focal adhesion turnover and focal adhesion kinase activation. In addition, SRC-3/AIB1 directly regulates transcription of matrix metalloproteinase (MMP)-2 and MMP-13 through its coactivation of AP-1 and PEA3. Taken together, these data suggest that SRC-3/AIB1 plays an essential role in prostate cancer cell invasion and metastasis.