title: Inhibition of Nrf2 enhances the anticancer effect of 6-O-angeloylenolin in lung adenocarcinoma.
abstract: 6-O-Angeloylenolin (6-OA), a sesquiterpene lactone isolated from Centipeda minima (L.) A. Br. (Compositae), has been used to treat respiratory diseases for centuries. However, whether and how 6-OA exerts anticancer effects against lung cancer remains to be elucidated. In this study, we showed that 6-OA markedly suppressed the cell viability and colony formation of lung cancer cells H1299 and A549, with no significant toxic effect on non-cancer cells HBE. Annexin V/7-AAD assay revealed that 6-OA induced cell apoptosis in dose- and time-dependent manners, which was further confirmed by the increased expression of cleaved caspase-3. To uncover the molecular mechanism how 6-OA exerts its anticancer effects, SILAC quantitative proteomics was performed to identify 6-OA-regulated proteins in lung cancer cells. Ingenuity Pathway Analysis revealed that these 6-OA-regulated proteins were mainly involved in Nrf2-mediated oxidative stress response, which was confirmed by the nuclear translocation of Nrf2 upon 6-OA treatment. Moreover, we found that 6-OA stimulated the accumulation of reactive oxygen species (ROS), whereas inhibition of ROS generation with N-acetyl l-cysteine could block the 6-OA-induced anticancer effects. Furthermore, blockade of cellular anti-oxidative system by Nrf2 knockdown significantly augmented the 6-OA-induced apoptosis. Taken together, we demonstrated that 6-OA exerts its anticancer effects by generating ROS, and inhibition of Nrf2 anti-oxidative system potentiated these effects. These results suggest that 6-OA may be used to treat lung cancer, with better outcome by combining with Nrf2 inhibitor to block Nrf2 pathway.
authors.affiliation: Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
authors.forename: Ru-Yuan
authors.initials: RY
authors.lastname: Yu
authors.affiliation: Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
authors.forename: Wei-Xia
authors.initials: WX
authors.lastname: Zhang
authors.affiliation: Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
authors.forename: Zhi-Hao
authors.initials: ZH
authors.lastname: Huang
authors.affiliation: Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China.
authors.forename: Hui-Fang
authors.initials: HF
authors.lastname: Hu
authors.affiliation: College of Pharmacy, Jinan University, Guangzhou 510632, China.
authors.forename: Yao-Lan
authors.initials: YL
authors.lastname: Li
authors.affiliation: Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China. Electronic address: libin2015@jnu.edu.cn.
authors.forename: Bin
authors.initials: B
authors.lastname: Li
authors.affiliation: Key Laboratory of Functional Protein Research of Guangdong Higher Education Institutes, Institute of Life and Health Engineering, College of Life Science and Technology, Jinan University, Guangzhou 510632, China. Electronic address: tqyhe@email.jnu.edu.cn.
authors.forename: Qing-Yu
authors.initials: QY
authors.lastname: He
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007783:Lactones / Q000494:pharmacology / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors*; D017382:Reactive Oxygen Species / Q000378:metabolism; D012717:Sesquiterpenes / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C531937:6-O-angeloylenolin; D000970:Antineoplastic Agents; D007783:Lactones; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes
keywords: 6-O-Angeloylenolin; Apoptosis; Nrf2; ROS; SILAC proteomics