Zhou Zhi-Wei, Li Xing-Xiao, He Zhi-Xu, Pan Shu-Ting, Yang Yinxue, Zhang Xueji, Chow Kevin, Yang Tianxin, Qiu Jia-Xuan, Zhou Qingyu, Tan Jun, Wang Dong, Zhou Shu-Feng
Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA ; Guizhou Provincial Key Laboratory for Regenerative Medicine, Stem Cell and Tissue Engineering Research Center and Sino-US Joint Laboratory for Medical Sciences, Guizhou Medical University, Guiyang, Guizhou, People's Republic of China.
Department of Pharmaceutical Sciences, College of Pharmacy, University of South Florida, Tampa, FL, USA.
Drug Des Devel Ther. 2015 Mar 12;9:1511-54. doi: 10.2147/DDDT.S75976. eCollection 2015.
Plumbagin (PLB) has been shown to have anticancer activities in animal models, but the role of PLB in prostate cancer treatment is unclear. This study aimed to investigate the effects of PLB on apoptosis and autophagy and the underlying mechanisms in human prostate cancer cell lines PC-3 and DU145. Our study has shown that PLB had potent pro-apoptotic and pro-autophagic effects on PC-3 and DU145 cells. PLB induced mitochondria-mediated apoptosis and autophagy in concentration- and time-dependent manners in both PC-3 and DU145 cells. PLB induced inhibition of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and p38 mitogen-activated protein kinase (MAPK) pathways and activation of 5'-AMP-dependent kinase (AMPK) as indicated by their altered phosphorylation, contributing to the pro-autophagic activity of PLB. Modulation of autophagy altered basal and PLB-induced apoptosis in both cell lines. Furthermore, PLB downregulated sirtuin 1 (Sirt1), and inhibition of Sirt1 enhanced autophagy, whereas the induction of Sirt1 abolished PLB-induced autophagy in PC-3 and DU145 cells. In addition, PLB downregulated pre-B cell colony-enhancing factor/visfatin, and the inhibition of pre-B cell colony-enhancing factor/visfatin significantly enhanced basal and PLB-induced apoptosis and autophagy in both cell lines. Moreover, reduction of intracellular reactive oxygen species (ROS) level attenuated the apoptosis- and autophagy-inducing effects of PLB on both PC-3 and DU145 cells. These findings indicate that PLB promotes apoptosis and autophagy in prostate cancer cells via Sirt1- and PI3K/Akt/mTOR-mediated pathways with contribution from AMPK-, p38 MAPK-, visfatin-, and ROS-associated pathways.
白花丹素（PLB）在动物模型中已显示出抗癌活性，但PLB在前列腺癌治疗中的作用尚不清楚。本研究旨在探讨PLB对人前列腺癌细胞系PC-3和DU145凋亡和自噬的影响及其潜在机制。我们的研究表明，PLB对PC-3和DU145细胞具有强大的促凋亡和促自噬作用。PLB在PC-3和DU145细胞中以浓度和时间依赖性方式诱导线粒体介导的凋亡和自噬。PLB诱导磷脂酰肌醇3激酶（PI3K）/蛋白激酶B（Akt）/雷帕霉素哺乳动物靶蛋白（mTOR）和p38丝裂原活化蛋白激酶（MAPK）通路的抑制以及5'-AMP依赖性激酶（AMPK）的激活，其磷酸化改变表明了这一点，这有助于PLB的促自噬活性。自噬的调节改变了两种细胞系中的基础凋亡和PLB诱导的凋亡。此外，PLB下调沉默调节蛋白1（Sirt1），抑制Sirt1增强自噬，而诱导Sirt1则消除了PLB在PC-3和DU145细胞中诱导的自噬。此外，PLB下调前B细胞集落增强因子/内脏脂肪素，抑制前B细胞集落增强因子/内脏脂肪素显著增强了两种细胞系中的基础凋亡和PLB诱导的凋亡及自噬。此外，细胞内活性氧（ROS）水平的降低减弱了PLB对PC-3和DU145细胞的凋亡和自噬诱导作用。这些发现表明，PLB通过Sirt1和PI3K/Akt/mTOR介导的途径促进前列腺癌细胞的凋亡和自噬，同时AMPK、p38 MAPK、内脏脂肪素和ROS相关途径也发挥了作用。
