Research Paper Volume 12, Issue 17 pp 17582—17600
Metformin suppresses Nrf2-mediated chemoresistance in hepatocellular carcinoma cells by increasing glycolysis
- 1 Department of Hepatobiliary and Pancreatic Surgery, Key Laboratory of Nanobiological Technology of Chinese Ministry of Health, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
- 2 Wuxi TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Wuxi 214071, Jiangsu, China
- 3 Hunan Yuantai Biotechnology Co., Ltd, Changsha 410000, Hunan, China
Received: February 17, 2020 Accepted: June 29, 2020 Published: September 14, 2020https://doi.org/10.18632/aging.103777
How to Cite
Copyright: © 2020 Cai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
The diabetes drug metformin has recently been shown to possess anti-cancer properties when used with other chemotherapeutic drugs. However, detailed mechanisms by which metformin improves cancer treatment are poorly understood. Here we provide evidence in HepG2 hepatocellular carcinoma cells that metformin sensitizes cisplatin-resistant HepG2 cells (HepG2/DDP) through increasing cellular glycolysis and suppressing Nrf2-dependent transcription. We show that metformin increases glucose uptake and enhances glucose metabolism through glycolytic pathway, resulting in elevated concentrations of intracellular NADPH and lactate. Consistently, high glucose medium suppresses Nrf2-dependent transcription and sensitizes HepG2/DDP cells to cisplatin. Elevated glycolysis was required for metformin to regulate Nrf2-dependent transcription and cisplatin sensitivity, as inhibition of glycolysis with 2-Deoxy-D-glucose (2-DG) significantly mitigates the beneficial effect of metformin. Together, our study has revealed an important biological process and gene transcriptional program underlying the beneficial effect of metformin on reducing chemo-resistance in HepG2 cells and provided new information on improving chemotherapy of liver cancers.