Review
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Biol Chem. Aug 26, 2015; 6(3): 148-161
Published online Aug 26, 2015. doi: 10.4331/wjbc.v6.i3.148
Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication
Minjong Lee, Jung-Hwan Yoon
Minjong Lee, Jung-Hwan Yoon, Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul 110-799, South Korea
Author contributions: Lee M and Yoon JH conceived and wrote this review.
Supported by Grant to Dr. Jung-Hwan Yoon; the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology, No. 20100007381; and by the Liver Research Foundation of Korea.
Conflict-of-interest statement: The authors declare no conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Jung-Hwan Yoon, MD, PhD, Professor, Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, South Korea. yoonjh@snu.ac.kr
Telephone: +82-2-20722228 Fax: +82-2-7436701
Received: April 19, 2015
Peer-review started: April 21, 2015
First decision: May 13, 2015
Revised: May 26, 2015
Accepted: July 21, 2015
Article in press: July 23, 2015
Published online: August 26, 2015
Processing time: 128 Days and 15.3 Hours
Abstract

Aerobic glycolysis, i.e., the Warburg effect, may contribute to the aggressive phenotype of hepatocellular carcinoma. However, increasing evidence highlights the limitations of the Warburg effect, such as high mitochondrial respiration and low glycolysis rates in cancer cells. To explain such contradictory phenomena with regard to the Warburg effect, a metabolic interplay between glycolytic and oxidative cells was proposed, i.e., the “reverse Warburg effect”. Aerobic glycolysis may also occur in the stromal compartment that surrounds the tumor; thus, the stromal cells feed the cancer cells with lactate and this interaction prevents the creation of an acidic condition in the tumor microenvironment. This concept provides great heterogeneity in tumors, which makes the disease difficult to cure using a single agent. Understanding metabolic flexibility by lactate shuttles offers new perspectives to develop treatments that target the hypoxic tumor microenvironment and overcome the limitations of glycolytic inhibitors.

Keywords: Hepatocellular carcinoma; Oxidative stress; Metabolic interventions; Aerobic glycolysis; Lactate

Core tip: The Warburg effect plays a vital role in cancer cell proliferation and survival, and contributes to the initiation of tumor metastasis. To adapt to rapidly changing microenvironment for survival such as from normoxia to hypoxia, cancer cells vary in metabolic phenotype; “metabolic flexibility”. Even in a hypoxic condition, oxidative cancer cells and/or stromal cells should theoretically exist to support the metabolic fuel for glycolytic cancer cells and handle lactate via the dynamic shuttle; “the reverse Warburg effect”. Treatments against tumor metabolism may aim to target two distinct metabolic pathways of glycolysis and mitochondrial oxidative phosphorylation.