Wang Xueni, Luo Xiaowei, Gan Xia, Chen Chunmei, Yang Zaizhun, Wen Jing, Fang Wenxuan, Huang Hailing, Gao Chenghai, Zhou Xuefeng, Feng Xiaotao, Liu Yonghong
CAS Key Laboratory of Tropical Marine Bio-resources and Ecology/Guangdong Key Laboratory of Marine Materia Medica, South China Sea Institute of Oceanology, Chinese Academy of Sciences, Guangzhou, China.
Institute of Marine Drugs, Guangxi University of Chinese Medicine, Nanning, China.
Front Pharmacol. 2022 Aug 10;13:920554. doi: 10.3389/fphar.2022.920554. eCollection 2022.
Advanced prostate cancer has a poor prognosis, and it is urgent to develop new effective drugs. 5'-Epiequisetin is a tetramic acid derivative which was isolated from a marine sponge-derived fungus in our previous study. In this study, 5'-epiequisetin showed cytotoxicity against four prostate cancer cell lines, namely, LNCaP, 22Rv1, DU145, and PC-3 cells, with the lowest IC value of 4.43 ± 0.24 μM in PC-3 cells. Further studies showed that it could dramatically regulate the clonal colony formation, apoptosis, and migration of PC-3 cells. In addition, flow cytometry data showed that 5'-epiequisetin could block the cell cycle at the G1 phase. Proteome profiler array and Western blot revealed that 5'-epiequisetin could regulate the expression of proteins responsible for cell proliferation, apoptosis, and migration. 5'-Epiequisetin regulated the expression of PI3K, Akt, phosphorylated Akt, and proteins which control the cell cycle. Meanwhile, 5'-epiequisetin upregulated expression of DR5 and cleave-caspase 3, which play important roles in the process of apoptosis. Moreover, when DR5 was silenced by small interfering RNA, the proportion of apoptotic cells induced by 5'-epiequisetin remarkably declined. In addition, 5'-epiequisetin downregulated the expression of survivin which plays a key role in the process of survival and apoptosis. 5'-Epiequisetin also impacted beta-catenin and cadherins, which were associated with cell migration. In addition, 5'-Epiequisetin significantly inhibited the progression of prostate cancer in mice, accompanied by regulating the protein expression of DR5, caspase 8, survivin, and cadherins . Taken together, these findings indicated that 5'-epiequisetin showed an anti-prostate cancer effect by inducing apoptosis and inhibiting cell proliferation and migration both and , suggesting a promising lead compound for the pharmacotherapy of prostate cancer.
晚期前列腺癌预后较差，开发新的有效药物迫在眉睫。5'-表异喹塞汀是一种四胺酸衍生物，在我们之前的研究中从一种海洋海绵来源的真菌中分离得到。在本研究中，5'-表异喹塞汀对四种前列腺癌细胞系，即LNCaP、22Rv1、DU145和PC-3细胞表现出细胞毒性，在PC-3细胞中的最低半数抑制浓度（IC）值为4.43±0.24μM。进一步研究表明，它可以显著调节PC-3细胞的克隆集落形成、凋亡和迁移。此外，流式细胞术数据显示，5'-表异喹塞汀可将细胞周期阻滞在G1期。蛋白质组分析阵列和蛋白质免疫印迹显示，5'-表异喹塞汀可调节负责细胞增殖、凋亡和迁移的蛋白质表达。5'-表异喹塞汀调节磷脂酰肌醇-3-激酶（PI3K）、蛋白激酶B（Akt）、磷酸化Akt以及控制细胞周期的蛋白质的表达。同时，5'-表异喹塞汀上调死亡受体5（DR5）和裂解的半胱天冬酶-3的表达，它们在凋亡过程中起重要作用。此外，当DR5被小干扰RNA沉默时，5'-表异喹塞汀诱导的凋亡细胞比例显著下降。此外，5'-表异喹塞汀下调在生存和凋亡过程中起关键作用的生存素的表达。5'-表异喹塞汀还影响与细胞迁移相关的β-连环蛋白和钙黏蛋白。此外，5'-表异喹塞汀显著抑制小鼠前列腺癌的进展，同时调节DR5、半胱天冬酶8、生存素和钙黏蛋白的蛋白质表达。综上所述，这些发现表明，5'-表异喹塞汀通过诱导凋亡以及抑制细胞增殖和迁移表现出抗前列腺癌作用，提示其是前列腺癌药物治疗中有前景的先导化合物。
