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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Oncol. | doi: 10.3389/fonc.2019.01282

Glucose Metabolites Exert Opposing Roles in Tumor Chemoresistance

 Chung-Yen Huang1, 2,  Ching-Ying Huang2, 3, Yu-Chen Pai2,  Ben-Ren Lin4, Tsung-Chun Lee5,  Pi-Hui Liang6 and  Linda C. Yu2*
  • 1National Taiwan University Hospital, Taiwan
  • 2Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taiwan
  • 3Department of Food and Applied Biotechnology, College of Agriculture and Natural Resources, National Chung Hsing University, Taiwan
  • 4Department of Surgery, National Taiwan University Hospital, Taiwan
  • 5Department of Internal Medicine, National Taiwan University Hospital, Taiwan
  • 6School of Pharmacy, College of Medicine, National Taiwan University, Taiwan

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 nonresponsive 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: Colorectal carcimoma, chemotherapy resistance, glycolytic pyruvate, ATP, Reactive oxgen species (ROS), necroptosis, cell cycle progression

Received: 22 Aug 2019; Accepted: 05 Nov 2019.

Copyright: © 2019 Huang, Huang, Pai, Lin, Lee, Liang and Yu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Linda C. Yu, Graduate Institute of Physiology, College of Medicine, National Taiwan University, Taipei, 100, Taiwan,