title: The ROS derived mitochondrial respirstion not from NADPH oxidase plays key role in Celastrol against angiotensin II-mediated HepG2 cell proliferation.
abstract: 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 (AT1) 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 (AT2) receptor without influencing NADPH oxidase activity. PD123319 as a special inhibitor of AT2R 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.
authors.affiliation: 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.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Binzhou Medical University Hospital, Binzhou, 256600, Shandong, China.
authors.forename: Rui-Wei
authors.initials: RW
authors.lastname: Gao
authors.affiliation: 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.
authors.forename: Miao
authors.initials: M
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Chun-Feng
authors.initials: CF
authors.lastname: Si
authors.affiliation: 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.
authors.forename: Yong-Peng
authors.initials: YP
authors.lastname: He
authors.affiliation: 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.
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.affiliation: 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.
authors.forename: Ying
authors.initials: Y
authors.lastname: Yang
authors.affiliation: 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 Otolaryngology-Head & Neck Surgery, Case Western Reserve University, Cleveland, OH, 44106, USA.
authors.forename: Qing-Yin
authors.initials: QY
authors.lastname: Zheng
authors.affiliation: 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. ytwcy@163.com.
authors.forename: Chao-Yun
authors.initials: CY
authors.lastname: Wang
mesh_terms: D000804:Angiotensin II / Q000235:genetics / Q000378:metabolism*; D017209:Apoptosis / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D056945:Hep G2 Cells; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D053978:Pentacyclic Triterpenes; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014315:Triterpenes / Q000494:pharmacology*
chemical_list: D053978:Pentacyclic Triterpenes; D017382:Reactive Oxygen Species; D014315:Triterpenes; D000804:Angiotensin II; D052250:Nitric Oxide Synthase Type III; D019255:NADPH Oxidases; C050414:celastrol
keywords: Angiotensin II; Angiotensin II type 2 receptor; Apoptosis; Celastrol; Mitochondrial function; NADPH oxidase