Sinularin, a natural product that purified from soft coral, exhibits anti-tumor effects against various human cancers. However, the mechanisms are not well understood. In this study, we demonstrated that Sinularin inhibited the viability of human prostate cancer cells in a dose-dependent manner and displayed significant cytotoxicity only at high concentration against normal prostate epithelial cell RWPE-1. Flow cytometry assay demonstrated that Sinularin induced tumor cell apoptosis. Further investigations revealed that Sinularin exerted anti-tumor activity through intrinsic apoptotic pathway along with up-regulation of pro-apoptotic protein Bax and PUMA, inhibition of anti-apoptotic protein Bcl-2, mitochondrial membrane potential collapses, and release of mitochondrial proteins. Furthermore, we illustrated that Sinularin induced cell apoptosis via up-regulating PUMA through inhibition of FOXO3 degradation by the ubiquitin–proteasome pathway. To explore how Sinularin suppress FOXO3 ubiquitin–proteasome degradation, we tested two important protein kinases AKT and ERK that regulate FOXO3 stabilization. The results revealed that Sinularin stabilized and up-regulated FOXO3 via inhibition of AKT- and ERK1/2-mediated FOXO3 phosphorylation and subsequent ubiquitin–proteasome degradation. Our findings illustrated the potential mechanisms by which Sinularin induced cell apoptosis and Sinularin may be applied as a therapeutic agent for human prostate cancer.

Sinularin 是一种从软珊瑚中提炼出来的天然产物，对多种人类癌症具有抗肿瘤作用。然而，其机制尚不清楚。在这项研究中，我们证明 Sinularin 以剂量依赖性方式抑制人前列腺癌细胞的活力，并且仅在高浓度时对正常前列腺上皮细胞 RWPE-1 表现出显着的细胞毒性。流式细胞术分析表明 Sinularin 诱导肿瘤细胞凋亡。进一步研究表明，Sinularin 通过内在凋亡途径、上调促凋亡蛋白 Bax 和 PUMA、抑制抗凋亡蛋白 Bcl-2、线粒体膜电位崩溃和线粒体蛋白释放来发挥抗肿瘤活性。此外，我们还发现 Sinularin 通过泛素-蛋白酶体途径抑制 FOXO3 降解，从而上调 PUMA，从而诱导细胞凋亡。为了探索 Sinularin 如何抑制 FOXO3 泛素蛋白酶体降解，我们测试了调节 FOXO3 稳定性的两种重要蛋白激酶 AKT 和 ERK。结果表明，Sinularin 通过抑制 AKT 和 ERK1/2 介导的 FOXO3 磷酸化以及随后的泛素蛋白酶体降解来稳定和上调 FOXO3。我们的研究结果说明了 Sinularin 诱导细胞凋亡的潜在机制，并且 Sinularin 可用作人类前列腺癌的治疗剂。