AR-PTEN Antagonism in Prostate Cell Growth And Apoptosis

AR-PTEN 拮抗前列腺细胞生长和凋亡

• 批准号: 6640169
• 负责人: WENLONG BAI
• 金额: $ 20.66万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2006-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6640169
• 关键词: androgen receptor; apoptosis; cell line; enzyme activity; enzyme linked immunosorbent assay; homeostasis; immunoprecipitation; isozymes; molecular oncology; neoplastic process; phosphomonoesterases; phosphorylation; prostate neoplasms; protein protein interaction; receptor binding; site directed mutagenesis; transfection /expression vector; transforming growth factors; tumor suppressor proteins; western blottings

DESCRIPTION (Provided by applicant): PTEN tumor suppressor and androgen receptor (AR) play important roles in prostate tumorigenesis by exerting opposite effects on prostate cancer (PCa) cells. Our studies demonstrated a mutual repression and selective dominance between PTEN and AR in the growth and the apoptosis of PCa cells. On one hand, PTEN and an inhibitor of 1-phosphoinositide 3-kinase (PI3K) repressed the transcriptional activity of AR as well as androgen-induced cell proliferation and production of prostate specific antigen. On the other hand, androgen protected PCa cells from PTEN-induced apoptosis in an AR-dependent manner. While the repression of the transcriptional activity of AR by PTEN is likely to involve the down regulation of AKT, androgen protects PCa cells from PTEN-induced apoptosis without an effect on AKT activity, demonstrating a differential involvement of AKT in antagonism between PTEN and AR. Our further investigation showed that the AR and FKHR (fork head in rhabdomyosarcoma), a mammalian homologue of the C. elegans Forkhead transcription factor Daf-16, forms a complex in PCa cells after androgen treatment and the complex formation resulted in the inhibition of FKHR transcriptional activity. Since we showed that AR is more active in the absence of functional PTEN, the loss of PTEN may induce prostate tumorigenesis by exposing prostate epithelial cells to unopposed AR activity. Similarly, excessive androgens may induce prostate tumorigenesis by blocking the apoptosis-promoting function of PTEN. Our data showing that the induction of apoptosis by the restored PTEN expression in LNCaP cells only occurred in the absence of androgens, imply that PTEN mutation or decreased expression may contribute to the resistance of PCa to androgen ablation and that the combinational inhibition of both PI3K/AKT and AR signaling could be an affective approach for the treatment of AR-positive PCa. The proposed studies are to elucidate the mechanism underlying the PTEN repression of AR activity by dissecting the biochemical steps between PTEN and AR and, through the study of AR-FKHR interaction, to define the mechanism underlying the androgen protection of PCa cells from PTEN-induced apoptosis. The studies about the mechanism underlying the AR-PTEN antagonism may provide a molecular foundation for new strategies to prevent prostate tumorigenesis or to treat the hormone refractory PCa by PTEN-based gene therapy.

描述（由申请人提供）：PTEN肿瘤抑制因子和雄激素受体（AR）通过对前列腺癌（PCa）细胞发挥相反作用，在前列腺肿瘤发生中发挥重要作用。我们的研究表明，在PCa细胞的生长和凋亡中，PTEN和AR之间存在相互抑制和选择性优势。一方面，PTEN和1-磷酸肌醇3-激酶（PI 3 K）抑制剂抑制AR的转录活性以及雄激素诱导的细胞增殖和前列腺特异性抗原的产生。另一方面，雄激素以AR依赖的方式保护PCa细胞免受PTEN诱导的凋亡。虽然PTEN对AR转录活性的抑制可能涉及AKT的下调，但雄激素保护PCa细胞免受PTEN诱导的凋亡而不影响AKT活性，表明AKT在PTEN和AR之间的拮抗作用中的差异参与。我们的进一步研究表明，AR和FKHR（横纹肌肉瘤中的叉头），一种与C。Elegans Forkhead转录因子Daf-16在雄激素处理后在PCa细胞中形成复合物，并且复合物的形成导致FKHR转录活性的抑制。由于我们表明AR在功能性PTEN缺失的情况下更活跃，因此PTEN的缺失可能会通过将前列腺上皮细胞暴露于无对抗的AR活性来诱导前列腺肿瘤发生。同样，过多的雄激素可能通过阻断PTEN的促前列腺增生功能而诱导前列腺肿瘤发生。我们的数据显示，在LNCaP细胞中，只有在雄激素缺乏的情况下才发生由恢复的PTEN表达诱导的凋亡，这意味着PTEN突变或表达降低可能有助于PCa对雄激素消融的抵抗，并且联合抑制PI 3 K/AKT和AR信号传导可能是治疗AR阳性PCa的有效方法。拟开展的研究旨在通过剖析PTEN和AR之间的生化步骤来阐明PTEN抑制AR活性的机制，并通过研究AR-FKHR相互作用来确定雄激素保护PCa细胞免受PTEN诱导的凋亡的机制。对AR-PTEN拮抗作用机制的研究可能为进一步研究以PTEN为基础的基因治疗方法预防前列腺癌的发生和治疗激素难治性前列腺癌提供分子基础。