title: Inhibition of glutamine utilization sensitizes lung cancer cells to apigenin-induced apoptosis resulting from metabolic and oxidative stress.
abstract: Recent studies have shown anticancer activity of apigenin by suppressing glucose transporter 1 (GLUT1) expression in cultured cancer cells; however, it is not clear whether apigenin can suppress glucose metabolism in lung cancer cells or sensitize them to inhibition of glutamine utilization-mediated apoptosis through metabolic and oxidative stress. We show that apigenin significantly decreases GLUT1 expression in mice. Furthermore, we demonstrate that apigenin induces growth retardation and apoptosis through metabolic and oxidative stress caused by suppression of glucose utilization in lung cancer cells. The underlying mechanisms were defined that the anticancer effects of apigenin were reversed by ectopic GLUT1 overexpression and galactose supplementation, through activation of pentose phosphate pathway-mediated NADPH generation. Importantly, we showed that severe metabolic stress using a glutaminase inhibitor, compound 968, was involved in the mechanism of sensitization by apigenin. Taken together, the combination of apigenin with inhibitors of glutamine metabolism may provide a promising therapeutic strategy for cancer treatment.
authors.affiliation: Department of Food Bioscience, College of Biomedical and Health Science, Konkuk University, Chungbuk, Chungju 380-701, Republic of Korea.
authors.forename: Yoon-Mi
authors.initials: YM
authors.lastname: Lee
authors.affiliation: Department of Biomedical Chemistry, College of Biomedical and Health Science, Konkuk University, Chungbuk, Chungju 380-701, Republic of Korea.
authors.forename: Gibok
authors.initials: G
authors.lastname: Lee
authors.affiliation: Department of Biomedical Chemistry, College of Biomedical and Health Science, Konkuk University, Chungbuk, Chungju 380-701, Republic of Korea.
authors.forename: Taek-In
authors.initials: TI
authors.lastname: Oh
authors.affiliation: Severance Integrative Research Institute for Cerebral and Cardiovascular Diseases (SIRIC), Yonsei University College of Medicine, Seodaemun-gu, Seoul 120-752, Republic of Korea.
authors.forename: Byeong Mo
authors.initials: BM
authors.lastname: Kim
authors.affiliation: Department of Biotechnology, College of Biomedical and Health Science, Konkuk University, Chungbuk, Chungju 380-701, Republic of Korea.
authors.forename: Do-Wan
authors.initials: DW
authors.lastname: Shim
authors.affiliation: Department of Biotechnology, College of Biomedical and Health Science, Konkuk University, Chungbuk, Chungju 380-701, Republic of Korea.
authors.forename: Kwang-Ho
authors.initials: KH
authors.lastname: Lee
authors.affiliation: Department of Biomedical Chemistry, College of Biomedical and Health Science, Konkuk University, Chungbuk, Chungju 380-701, Republic of Korea.
authors.forename: Young Jun
authors.initials: YJ
authors.lastname: Kim
authors.affiliation: Department of Biomedical Chemistry, College of Biomedical and Health Science, Konkuk University, Chungbuk, Chungju 380-701, Republic of Korea.
authors.forename: Beong Ou
authors.initials: BO
authors.lastname: Lim
authors.affiliation: Department of Biomedical Chemistry, College of Biomedical and Health Science, Konkuk University, Chungbuk, Chungju 380-701, Republic of Korea.
authors.forename: Ji-Hong
authors.initials: JH
authors.lastname: Lim
mesh_terms: D000818:Animals; D047310:Apigenin / Q000008:administration & dosage; D017209:Apoptosis / Q000187:drug effects*; D053119:Benzophenanthridines / Q000008:administration & dosage; D045744:Cell Line, Tumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D051272:Glucose Transporter Type 1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D005973:Glutamine / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009249:NADP / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D053119:Benzophenanthridines; D051272:Glucose Transporter Type 1; D017382:Reactive Oxygen Species; C495677:SLC2A1 protein, human; C000598981:compound 968; D005973:Glutamine; D009249:NADP; D047310:Apigenin