Glucose Metabolites Exert Opposing Roles in Tumor Chemoresistance

Chung-Yen Huang; Ching-Ying Huang; Yu-Chen Pai; Been-Ren Lin; Tsung-Chun Lee; Pi-Hui Liang; Linda Chia-Hui Yu

doi:10.3389/fonc.2019.01282

Glucose Metabolites Exert Opposing Roles in Tumor Chemoresistance

Front Oncol. 2019 Nov 21:9:1282. doi: 10.3389/fonc.2019.01282. eCollection 2019.

Authors

Chung-Yen Huang^{1

2}, Ching-Ying Huang^{1

3}, Yu-Chen Pai¹, Been-Ren Lin⁴, Tsung-Chun Lee⁵, Pi-Hui Liang⁶, Linda Chia-Hui Yu¹

Affiliations

¹ Graduate Institute of Physiology, National Taiwan University College of Medicine, Taipei, Taiwan.
² School of Medicine, National Taiwan University College of Medicine, Taipei, Taiwan.
³ Department of Food Science and Biotechnology, National Chung-Hsing University, Taichung City, Taiwan.
⁴ Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.
⁵ Department of Internal Medicine, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan.
⁶ School of Pharmacy, National Taiwan University, Taipei, Taiwan.

Abstract

Reprogrammed glucose metabolism and increased glycolysis have been implicated in tumor chemoresistance. The aim was to investigate the distinct roles of the glucose metabolites pyruvate and ATP in chemoresistance mechanisms, including cell death and proliferation. Our data showed higher glucose transporters in colorectal cancer (CRC) from non-responsive patients than those responsive to chemotherapy. Human CRC cell lines exposed to 5-fluorouracil (5-FU) displayed elevated cell viability and larger tumors in xenograft mouse models if cultured in high-glucose medium. Glucose conferred resistance to 5-FU-induced necroptosis via pyruvate scavenging of mitochondrial free radicals, whereas ATP replenishment had no effect on cell death. Glucose attenuated the 5-FU-induced G0/G1 shift but not the S phase arrest. Opposing effects were observed by glucose metabolites; ATP increased while pyruvate decreased the G0/G1 shift. Lastly, 5-FU-induced tumor spheroid destruction was prevented by glucose and pyruvate, but not by ATP. Our finding argues against ATP as the main effector for glucose-mediated chemoresistance and supports a key role of glycolytic pyruvate as an antioxidant for dual modes of action: necroptosis reduction and a cell cycle shift to a quiescent state.

Keywords: cell cycle progression; chemotherapy resistance; colorectal carcinoma; glycolytic pyruvate; liposomal ATP; necroptotic death; reactive oxidative species.