蛋白酶体相关去泛素化酶抑制剂的发现及其在肿瘤治疗中的作用

Ubiquitin-proteasome system (UPS) mediates the degradation of most of the proteins in the cell,thus becoming an important molecular target in cancer therapy. Proteasome inhibitor bortezomib has been approved by FDA for the treatment of multiple myeloma. Compared with 20S proteasome, proteasome-associated deubiquitinase (DUB) has more potential to selectively and specifically degrade cellular proteins and now is also becoming an important target of cancer therapy. Therefore, it is of great importance to find novel proteasome-associated DUB inhibitors. It is known that metal-containing compounds like copper complex could inhibit proteasome function, but the molecular target remains unclear. It has been hypothesized that metal compounds like copper or zinc complex inhibit the proteasome by a mechanism that is distinct to the clinically used drug bortezomib, targeting the 19S rather than the 20S proteasome, but this hypothesis has not been tested. We recently confirmed that copper complex like copper pyrithione induced cytotoxicity by targeting DUBs. But it was further found that copper compound like CuPT did not selectively inhibit proteasome-associated DUBs and cancer cell growth, therefore more metal-containing compounds were compared in our previous studies. Unexpectedly, it was found that platinum (Pt) compound like PtPT more selectively inhibit proteasome-associated DUBs and induce cancer cell death compared with other metal-containing compounds. In the current study, the DUB inhibiting effect and apoptosis induction mechanism of platinum-containing compound were investigated, and the anti-tumor effects were also studied in both cisplatin- and bortezomib-resistant tumor models.

泛素-蛋白酶体系统(UPS)介导细胞内多种蛋白质降解，并已成为肿瘤治疗的重要靶点。与20S蛋白酶体相比，蛋白酶体相关去泛素化酶(DUB)对蛋白的降解更具有选择性和特异性，目前成为抗肿瘤研究的热点。发现新的DUB抑制剂对肿瘤治疗具有重要意义。金属离子化合物对UPS的抑制效应明确，但其作用靶点不清，有报道推测其可能作用于蛋白酶体相关DUB，但一直未得到实验证实。我们前期发现，金属离子化合物如铜离子敏感作用于DUBs，其介导的DUB抑制是其抗肿瘤效应的关键靶点，但随后发现其对细胞总DUBs和蛋白酶体相关DUBs，以及正常和肿瘤细胞作用的选择性较差，未来成药性不理想；进一步对多种金属离子化合物进行比较，发现铂离子化合物对蛋白酶体相关DUBs和肿瘤细胞具有较好的选择性。本项目全面论证铂离子化合物对DUB的抑制作用及其诱导细胞死亡的机理，并探讨其克服顺铂耐药和蛋白酶体抑制剂硼替佐米耐药的抗肿瘤效应。

泛素-蛋白酶体系统(UPS)介导细胞内多种蛋白质降解，并已成为肿瘤治疗的重要靶点。与20S蛋白酶体相比，蛋白酶体相关去泛素化酶(DUB)对蛋白的降解更具有选择性和特异性，目前成为抗肿瘤研究的热点。发现新的DUB抑制剂对肿瘤治疗具有重要意义。我们发现并深入研究了金属离子化合物包括PtPT、NiPT、AuPT等调控19S蛋白酶体相关去泛素化酶USP14和UCHL5的作用机制，并明确可能为其抗肿瘤主要靶点；并进一步阐明了19S蛋白酶体相关去泛素化酶USP14和UCHL5金属离子抑制剂在CML治疗中的作用机制，发现与蛋白酶体功能抑制及其诱导细胞Caspase系统活化，切割BCR-ABL导致P-BCR-ABL减少所致；研究证实去泛素化酶USP14调控雄激素受体(AR)泛素化降解是其调节雄激素依赖前列腺癌和AR阳性乳腺癌生长的主要机制。综上所述，我们的研究发现了一类新的蛋白酶体相关DUB抑制剂，同时也揭示了金属离子作用于蛋白酶体系统的分子靶点。