title: NOX2-ROS-HIF-1α signaling is critical for the inhibitory effect of oleanolic acid on rectal cancer cell proliferation.
abstract: Rectal cancer is the second leading cause of cancer mortality in the western countries and accounts for 10% incidence and mortality of cancer in the whole world. Drug resistance and severe toxicity severely limited the efficiency of chemotherapy of rectal cancer. Oleanolic acid (OA) is a natural triterpenoid and an aglycone of many saponins. In the present study, we aimed to investigate the effect of OA on rectal cancer cell proliferation and its possible mechanism. We showed that OA concentration-dependently inhibited cell proliferation in HCT-15, HT-29, HCT-8 and Colo 205 human rectal cancer cell lines. OA significantly increased reactive oxygen species (ROS) generation and NADPH oxidase 2 (NOX2) expression in a concentration-dependent manner. In HCT-15 and HT-29 cells, siNOX2 notably suppressed OA-induced ROS generation, inhibition of cell proliferation, increase of S phase cell population and decrease of cyclin D1 and CDK2 expression. OA markedly decreased hypoxia-inducible factor 1α (HIF-1α) expression in HCT-15 and HT-29 cells in a concentration-dependent manner. Overexpression of HIF-1α significantly suppressed OA-induced inhibition of cell proliferation, increase of S phase cell population and decrease of cyclin D1 and CDK2 expression. Inhibition of NOX2 by siRNA notably blocked OA-induced suppression of HIF-1α expression. Our findings provide novel insights into OA-induced inhibition of rectal cancer cell proliferation and highlight NOX2/ROS/HIF-1α axis as a novel therapeutic target for the treatment of rectal cancer.
authors.affiliation: Department of General Surgery, Xi'an Ninth Hospital, Xi'an 710054, Shaanxi Province, China.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Radiology, Xi'an Ninth Hospital, Xi'an 710054, Shaanxi Province, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Han
authors.affiliation: Department of General Surgery, Xi'an Ninth Hospital, Xi'an 710054, Shaanxi Province, China.
authors.forename: Kongliang
authors.initials: K
authors.lastname: Luo
authors.affiliation: Department of General Surgery, Xi'an Ninth Hospital, Xi'an 710054, Shaanxi Province, China.
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Ren
authors.affiliation: Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, 710032, Shaanxi Province, China. Electronic address: lc121123@163.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Cai
authors.affiliation: Division of Digestive Surgery, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, 127 West Changle Road, Xi'an, 710032, Shaanxi Province, China. Electronic address: lisun31@163.com.
authors.forename: Li
authors.initials: L
authors.lastname: Sun
mesh_terms: D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism*; D009828:Oleanolic Acid / Q000494:pharmacology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012004:Rectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008562:Membrane Glycoproteins; D017382:Reactive Oxygen Species; D009828:Oleanolic Acid; C056558:CYBB protein, human; D000074662:NADPH Oxidase 2; D019255:NADPH Oxidases
keywords: HIF-1α; NOX2; Oleanolic acid; Proliferation; Rectal cancer