Inhibition of glutamine utilization sensitizes lung cancer cells to apigenin-induced apoptosis resulting from metabolic and oxidative stress

Lee,Yoon-Mi; Lee,Gibok; Oh,Taek-In; Kim,Byeong  Mo; Shim,Do-Wan; Lee,Kwang-Ho; Kim,Young  Jun; Lim,Beong  Ou; Lim,Ji-Hong

doi:10.3892/ijo.2015.3243

Inhibition of glutamine utilization sensitizes lung cancer cells to apigenin-induced apoptosis resulting from metabolic and oxidative stress

Authors:
- Yoon-Mi Lee
- Gibok Lee
- Taek-In Oh
- Byeong Mo Kim
- Do-Wan Shim
- Kwang-Ho Lee
- Young Jun Kim
- Beong Ou Lim
- Ji-Hong Lim
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Affiliations: Department of Food Bioscience, College of Biomedical and Health Science, Konkuk University, Chungbuk, Chungju 380-701, Republic of Korea, Department of Biomedical Chemistry, College of Biomedical and Health Science, Konkuk University, Chungbuk, Chungju 380-701, Republic of Korea, Severance Integrative Research Institute for Cerebral and Cardiovascular Diseases (SIRIC), Yonsei University College of Medicine, Seodaemun-gu, Seoul 120-752, Republic of Korea, Department of Biotechnology, College of Biomedical and Health Science, Konkuk University, Chungbuk, Chungju 380-701, Republic of Korea
Published online on: November 11, 2015 https://doi.org/10.3892/ijo.2015.3243
Pages: 399-408

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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.

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