Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication

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.