title: ERK inhibition sensitizes cancer cells to oleanolic acid-induced apoptosis through ERK/Nrf2/ROS pathway.
abstract: Oleanolic acid (OA) is a natural triterpenoid that is widely distributed in edible and medicinal plants. OA exerts anti-tumor activity on a wide range of cancer cells primarily through inducing apoptosis. Dysregulated ERK signaling is closely complicated in the biology of cancer, such as metastasis, proliferation, and survival, and it can be activated by various stimuli. In this study, we found that OA induced the activation of ERK in cancer cells. ERK activation compromised the apoptosis induced by OA. Blocking ERK activation by U0126 or siRNAs was able to potentiate the pro-apoptotic activity of OA on cancer cells. OA was shown to promote ERK-dependent Nrf2 expression in cancer cells, and in turn, Nrf2 expression was able to suppress OA-induced ROS generation. Blockade of Nrf2 expression was able to increase ROS levels and apoptotic death in cancer cells. In conclusion, we provided evidences that ERK activation is a mechanism underlying the resistance of cancer cells to OA-induced apoptosis and targeting ERK is a promising strategy to enhance the anti-tumor efficacy of OA.
authors.affiliation: College of Medicine, Qingdao University, 38 Dengzhou Road, Qingdao, 266021, China.
authors.forename: Jia
authors.initials: J
authors.lastname: Liu
authors.affiliation: College of Medicine, Qingdao University, 38 Dengzhou Road, Qingdao, 266021, China.|The Affiliated Hospital to Qingdao University, Qingdao, 266003, China.
authors.forename: Leina
authors.initials: L
authors.lastname: Ma
authors.affiliation: College of Medicine, Qingdao University, 38 Dengzhou Road, Qingdao, 266021, China.
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.affiliation: College of Medicine, Qingdao University, 38 Dengzhou Road, Qingdao, 266021, China.
authors.forename: Jianxun
authors.initials: J
authors.lastname: Wang
authors.affiliation: College of Medicine, Qingdao University, 38 Dengzhou Road, Qingdao, 266021, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Yu
authors.affiliation: College of Medicine, Qingdao University, 38 Dengzhou Road, Qingdao, 266021, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Gong
authors.affiliation: College of Medicine, Qingdao University, 38 Dengzhou Road, Qingdao, 266021, China.
authors.forename: Aiguo
authors.initials: A
authors.lastname: Ma
authors.affiliation: Yellow Sea Fisheries Research Institute, Chinese Academy of Fishery Sciences, 106 Nanjing Road, Qingdao, 266071, China. zhenglh@ysfri.ac.cn.
authors.forename: Lanhong
authors.initials: L
authors.lastname: Zheng
authors.affiliation: College of Medicine, Qingdao University, 38 Dengzhou Road, Qingdao, 266021, China. ajgqdfy@163.com.
authors.forename: Hui
authors.initials: H
authors.lastname: Liang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002070:Butadienes / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D051267:NF-E2-Related Factor 2 / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D009828:Oleanolic Acid / Q000494:pharmacology*; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D009570:Nitriles; D017382:Reactive Oxygen Species; C113580:U 0126; D009828:Oleanolic Acid; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Apoptosis; ERK; Nrf2; Oleanolic acid