蛋白酶体相关去泛素化酶USP14抑制剂调控前列腺癌的生长及其机制

The ubiquitin-proteasome system (UPS)-mediated degradation pathway has been considered to be an important target for cancer therapy. A number of studies suggested that the inhibition of USP14 enhanced proteasome function. Androgen receptor (AR), a vital target of prostate cancers treatment, is primarily degraded via proteasome pathway. We have identified USP14 as a novel regulator of AR, inhibiting the degradation of AR via deubiquitinating this oncoprotein in the androgen responsive prostate cancer cells. Recently we also found that platinum(Pt) compound Pt-DSF can attenuate the accumulation of ubiquitin conjugates, which was blocked by bortezomib without inhibiting proteolytic activities of CT-like subunit in 20S core particle and DUBs activity in cytoplasm, computer virtual space docking show Pt -DSF may interact with the catalytic center of USP14. Therefore, we hypothesized Pt-DSF may control the proliferation of prostate cancers via targeting the degradation of AR mediated by USP14 inhibition. Our study aims to explore the molecular mechanisms of Pt-DSF in growth-inhibitory effects of AR-dependent prostate cancers by targeting USP14, providing a clear rationale for the development of a novel strategy for prostate cancer treatment and prevention.

泛素-蛋白酶体系统已成为抗肿瘤治疗的重要靶点。选择抑制蛋白酶体相关去泛素化酶（DUB）USP14的活性可以增强蛋白酶体活性，促进蛋白降解。雄激素受体（AR）是前列腺癌治疗的主要靶点，AR通过泛素-蛋白酶体途径降解，前期研究表明USP14通过调控AR的泛素化降解调节激素依赖性前列腺癌生长；前期还发现，双硫仑铂离子络合物Pt-DSF引起肿瘤细胞泛素化蛋白减少，这种作用可被20S蛋白酶体抑制剂硼替佐米逆转，但Pt-DSF不影响蛋白酶体糜蛋白酶亚基活性，也不影响总的DUB活性，计算机空间对接显示Pt-DSF可与USP14的催化中心相互作用。由此，我们提出假说：Pt-DSF通过抑制去泛素化酶USP14调控AR泛素化降解调节前列腺癌生长。本研究拟以前列腺癌为研究对象，通过不同的手段，探讨Pt-DSF介导的USP14去泛素化酶活性抑制与其抗AR依赖性前列腺癌之间的关系及机制，为前列腺癌防治提供新的手段。

泛素-蛋白酶体系统已成为抗肿瘤治疗的重要靶点。选择抑制蛋白酶体相关去泛素化酶（DUB）USP14的活性可以促进蛋白降解。雄激素受体（AR）是前列腺癌治疗的主要靶点，AR通过泛素-蛋白酶体途径降解，前期研究表明USP14通过调控AR的泛素化降解调节激素依赖性前列腺癌生长。发现新的USP14抑制剂对前列腺癌治疗具有重要意义。我们发现并深入研究了多个USP14抑制剂在前列腺癌和其它肿瘤中的作用，并阐释了其作用机制。研究证实USP14抑制剂金诺芬通过调控AR泛素化降解是其调节雄激素依赖前列腺癌生长的主要机制；发现新一类的USP14抑制剂AgDT；发现USP14抑制剂PtPT抑制ER阳性乳腺癌生长的作用机制；发现抑制USP14的活性联合恩杂鲁胺可以促进AR的降解增强恩杂鲁胺抗肿瘤活性；发现USP10和USP13抑制剂Spautin-1抗前列腺癌的新机制；发现USP14抑制剂调控铁死亡和自噬的作用机制；发现选择性诱导AR-V7蛋白降解的新型化学小分子药物。综上所述，我们的研究证实了USP14抑制剂抗前列腺癌和其它肿瘤中的作用及分子机制，为USP14抑制剂治疗肿瘤提供了实验依据。