AR-PTEN Antagonism in Prostate Cell Growth And Apoptosis

描述（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）细胞施加相反的作用，在前列腺肿瘤发生中发挥重要作用。我们的研究表明PTEN和AR在PCa细胞的生长和凋亡中相互抑制和选择性优势。一方面，PTEN和1-磷酸肌苷激酶（PI3K）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的活性，这表明AKT在PTEN和AR的拮抗中有不同的参与。我们进一步的研究表明，AR和FKHR（横纹肌肉瘤叉头），一种线虫叉头转录因子Daf-16的哺乳动物同源物，雄激素处理后，在PCa细胞中形成复合物，复合物的形成导致FKHR转录活性受到抑制。由于我们发现AR在缺乏功能性PTEN的情况下更活跃，PTEN的缺失可能通过将前列腺上皮细胞暴露于无对抗的AR活性中诱导前列腺肿瘤发生。同样，过多的雄激素可能通过阻断PTEN的促凋亡功能而诱导前列腺肿瘤的发生。我们的数据显示，LNCaP细胞中PTEN表达恢复诱导凋亡仅发生在缺乏雄激素的情况下，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PI3K/AKT和AR信号可能是治疗AR阳性PCa的有效方法。本研究拟通过剖析PTEN与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。AR-PTEN拮抗机制的研究可能为预防前列腺肿瘤发生的新策略或基于pten的基因治疗激素难治性前列腺癌提供分子基础。

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.