Department of Biomedical Sciences, University of Illinois, Rockford, IL, United States of America.
Department of Biomedical Sciences, University of Illinois, Rockford, IL, United States of America.
Toxicol Appl Pharmacol. 2020 Aug 15;401:115071. doi: 10.1016/j.taap.2020.115071. Epub 2020 May 23.
Prostate Cancer (PCa) is the second most common cancer among men in United States after skin cancer. Conventional chemotherapeutic drugs available for PCa treatment are limited due to toxicity and resistance issues. Therefore, there is an urgent need to develop more effective treatment for advanced PCa. In this current study, we focused on evaluating the anti-cancer efficacy of Eprinomectin (EP), a novel avermectin analog against PC3 metastatic PCa cells. EP displayed robust inhibition of cell viability of PC3 cells in addition to suppressing the colony formation and wound healing capabilities. Our study showed that EP targets PC3 cells via inducing ROS and apoptosis activation. EP treatment enforces cell cycle arrest at G0/G1 phase via targeting cyclin-dependent kinase 4 (CDK4) and subsequent induction of apoptosis in PC3 cells. At the molecular level, EP effectively inhibited the expression of various cancer stem cell markers such as ALDH1, Sox-2, Nanog, Oct3/4 and CD44. Interestingly, EP also inhibited the activity of alkaline phosphatase, a maker of pluripotent stem cells. Of note, EP treatment resulted in the translocation of β-catenin from the nucleus to the cytoplasm indicating that EP antagonizes Wnt/β-catenin signaling pathway. Western blotting analysis revealed that EP downregulated the expression of key cell cycle markers such as cyclin D1, cyclin D3, CDK4, and c-Myc. In addition, EP inhibited the anti-apoptotic markers such as Mcl-1, XIAP, c-IAP1 and survivin in PC3 cells. On the other hand, EP treatment resulted in the activation of pH2A.X, Bad, caspase-9, caspase-3 and cleavage of PARP1. Taken together, our data suggests that EP is a potential agent to treat advanced PCa cells via modulating apoptosis signaling.
前列腺癌（PCa）是美国男性中仅次于皮肤癌的第二大常见癌症。现有的用于 PCa 治疗的常规化疗药物由于毒性和耐药性问题而受到限制。因此，迫切需要开发更有效的治疗晚期 PCa 的方法。在本研究中，我们专注于评估埃普利诺菌素（EP）作为一种新型阿维菌素类似物对 PC3 转移性 PCa 细胞的抗癌功效。EP 对 PC3 细胞的活力具有强大的抑制作用，除了抑制集落形成和伤口愈合能力外。我们的研究表明，EP 通过诱导 ROS 和细胞凋亡激活来靶向 PC3 细胞。EP 通过靶向细胞周期蛋白依赖性激酶 4（CDK4）并随后诱导 PC3 细胞凋亡，使细胞周期停滞在 G0/G1 期。在分子水平上，EP 有效地抑制了各种癌症干细胞标志物的表达，如 ALDH1、Sox-2、Nanog、Oct3/4 和 CD44。有趣的是，EP 还抑制了碱性磷酸酶的活性，碱性磷酸酶是多能干细胞的标志物。值得注意的是，EP 处理导致β-连环蛋白从细胞核转位到细胞质，表明 EP 拮抗 Wnt/β-连环蛋白信号通路。Western blot 分析显示，EP 下调了细胞周期标志物如 cyclin D1、cyclin D3、CDK4 和 c-Myc 的表达。此外，EP 抑制了 PC3 细胞中的抗凋亡标志物，如 Mcl-1、XIAP、c-IAP1 和 survivin。另一方面，EP 处理导致 pH2A.X、Bad、caspase-9、caspase-3 和 PARP1 的切割被激活。综上所述，我们的数据表明，EP 通过调节凋亡信号通路是治疗晚期 PCa 细胞的潜在药物。
