Liu Xin, Gao Rui-Wei, Li Miao, Si Chun-Feng, He Yong-Peng, Wang Min, Yang Ying, Zheng Qing-Yin, Wang Chao-Yun
Key Laboratory of Traditional Chinese Medicine Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine, School of Pharmaceutical Sciences, Binzhou Medical University, Yantai, 264003, Shandong, China.
Department of Pediatrics, Binzhou Medical University Hospital, Binzhou, 256600, Shandong, China.
Apoptosis. 2016 Nov;21(11):1315-1326. doi: 10.1007/s10495-016-1294-6.
Angiotensin II (AngII) is an important factor that promotes the proliferation of cancer cells, whereas celastrol exhibits a significant antitumor activity in various cancer models. Whether celastrol can effectively suppress AngII mediated cell proliferation remains unknown. In this study, we studied the effect of celastrol on AngII-induced HepG2 cell proliferation and evaluated its underlying mechanism. The results revealed that AngII was able to significantly promote HepG2 cell proliferation via up-regulating AngII type 1 (AT) receptor expression, improving mitochondrial respiratory function, enhancing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity, increasing the levels of reactive oxygen species (ROS) and pro-inflammatory cytokines. The excess ROS from mitochondrial dysfunction is able to cause the apoptosis of tumor cells via activating caspase3 signal pathway. In addition, the reaction between NO and ROS results in the formation of peroxynitrite (ONOO), and then promoting cell damage. celastrol dramatically enhanced ROS generation, thereby causing cell apoptosis through inhibiting mitochodrial respiratory function and boosting the expression levels of AngII type 2 (AT) receptor without influencing NADPH oxidase activity. PD123319 as a special inhibitor of ATR was able to effectively decreased the levels of inflammatory cytokines and endothelial nitric oxide synthase (eNOS) activity, but only partially attenuate the effect of celastrol on AnII mediated HepG2 cell proliferation. Thus, celastrol has the potential for use in liver cancer therapy. ROS derived from mitochondrial is an important factor for celastrol to suppress HepG2 cell proliferation.
血管紧张素 II（AngII）是促进癌细胞增殖的重要因素，而雷公藤红素在多种癌症模型中表现出显著的抗肿瘤活性。雷公藤红素是否能有效抑制 AngII 介导的细胞增殖尚不清楚。在本研究中，我们研究了雷公藤红素对 AngII 诱导的 HepG2 细胞增殖的影响，并评估了其潜在机制。结果显示，AngII 能够通过上调 1 型血管紧张素 II（AT）受体表达、改善线粒体呼吸功能、增强烟酰胺腺嘌呤二核苷酸磷酸（NADPH）氧化酶活性、增加活性氧（ROS）和促炎细胞因子水平，显著促进 HepG2 细胞增殖。线粒体功能障碍产生的过量 ROS 能够通过激活半胱天冬酶 3 信号通路导致肿瘤细胞凋亡。此外，NO 与 ROS 反应导致过氧亚硝酸盐（ONOO）形成，进而促进细胞损伤。雷公藤红素显著增强 ROS 生成，从而通过抑制线粒体呼吸功能和提高 2 型血管紧张素 II（AT）受体表达水平导致细胞凋亡，而不影响 NADPH 氧化酶活性。PD123319 作为 ATR 的特异性抑制剂，能够有效降低炎症细胞因子水平和内皮型一氧化氮合酶（eNOS）活性，但只能部分减弱雷公藤红素对 AngII 介导的 HepG2 细胞增殖的影响。因此，雷公藤红素具有用于肝癌治疗的潜力。线粒体产生的 ROS 是雷公藤红素抑制 HepG2 细胞增殖的重要因素。
