The Warburg effect in tumor progression: mitochondrial oxidative metabolism as an anti-metastasis mechanism

Abstract

Compared to normal cells, cancer cells strongly upregulate glucose uptake and glycolysis to give rise to increased yield of intermediate glycolytic metabolites and the end product pyruvate. Moreover, glycolysis is uncoupled from the mitochondrial tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in cancer cells. Consequently, the majority of glycolysis-derived pyruvate is diverted to lactate fermentation and kept away from mitochondrial oxidative metabolism. This metabolic phenotype is known as the Warburg effect. While it has become widely accepted that the glycolytic intermediates provide essential anabolic support for cell proliferation and tumor growth, it remains largely elusive whether and how the Warburg metabolic phenotype may play a role in tumor progression. We hereby review the cause and consequence of the restrained oxidative metabolism, in particular in the context of tumor metastasis. Cells change or lose their extracellular matrix during the metastatic process. Inadequate/inappropriate matrix attachment generates reactive oxygen species (ROS) and causes a specific type of cell death, termed anoikis, in normal cells. Although anoikis is a barrier to metastasis, cancer cells have often acquired elevated threshold for anoikis and hence heightened metastatic potential. As ROS are inherent byproducts of oxidative metabolism, forced stimulation of glucose oxidation in cancer cells raises oxidative stress and restores cells' sensitivity to anoikis. Therefore, by limiting the pyruvate flux into mitochondrial oxidative metabolism, the Warburg effect enables cancer cells to avoid excess ROS generation from mitochondrial respiration and thus gain increased anoikis resistance and survival advantage for metastasis. Consistent with this notion, pro-metastatic transcription factors HIF and Snail attenuate oxidative metabolism, whereas tumor suppressor p53 and metastasis suppressor KISS1 promote mitochondrial oxidation. Collectively, these findings reveal mitochondrial oxidative metabolism as a critical suppressor of metastasis and justify metabolic therapies for potential prevention/intervention of tumor metastasis.

Keywords: Anoikis; Glycolysis; Metastasis; OXPHOS; ROS; Warburg effect.

Fig. 1. Schematic illustration of glucose metabolism in normal and cancer cells under normoxia

(left) In normal (quiescent) cells, glucose is converted to pyruvate through glycolysis, and most pyruvate enters mitochondrial oxidative metabolism for efficient energy generation (in the form of ATP). Glucose is predominantly used for energy production. High levels of ATP attenuate glycolysis via feedback inhibition. (right) Cancer cells dramatically increase glucose uptake and glycolysis (indicated by bold arrows). A significant portion of glucose carbon is diverted to biosynthetic pathways to fuel cell proliferation. Pyruvate is preferentially shunted to lactate, resulting in increased lactate production. Oxidative metabolism persists, but is uncoupled from increased glycolysis. The respiration byproducts ROS exhibit anti-metastasis activity, which may explain why cancer cells keep glucose oxidation in check. The flux of glucose carbon is indicated by green arrows (The thickness of arrows reflects the relative amount of the flow). Major mitochondrial products are depicted in red; metastatic regulators are in purple; regulatory steps are in blue; and the metabolic effects on cancer are in pink.

Fig. 2. Normal cells reprogram metabolism and redox regulation to counter oxidative stress induced by matrix detachment

Although they undergo anoikis, detached normal cells shut down glucose oxidation and increase antioxidant capacity by upregulating of PDK4 and MnSOD, respectively, to contain ROS and delay anoikis.

Fig. 3. Expression of PDKs and MnSOD in breast cancer correlates with tumor grades and unfavorable clinical outcome

A. Correlation between expression of PDK1, PDK3, and MnSOD, and tumor histological grades in breast cancer based on the dataset GSE3494 (n=251). B. Higher levels of PDK1, PDK3, and MnSOD predict worse relapse-free survival (RFS) in a large cohort of breast cancer patients (n=3455). Analysis was performed using the webtool developed by [40].