Novel Role of NOX in Supporting Aerobic Glycolysis in Cancer Cells with Mitochondrial Dysfunction and as a Potential Target for Cancer Therapy

Weiqin Lu,Zhao Chen,Feng Wang,Hua Wang,Jinsong Liu,Michael J Keating,Wallace Mckeehan,Yongde Luo,Gang Chen,Huamin Wang,Helene Pelicano,Yumin Hu,Hui Zhang,Li Feng,Peng Huang,Manfred Schartl

doi:10.1371/journal.pbio.1001326

Abstract

Author SummaryGlycolysis is a cytoplasmic metabolic process that produces energy from glucose. In normal cells, the rate of glycolysis is low, and glycolysis products are further processed in the mitochondria via oxidative phosphorylation, a very efficient energy-producing process. Cancer cells, however, display higher levels of glycolysis followed by cytoplasmic fermentation, and reduced levels of oxidative phosphorylation. It was thought that increased glycolysis is associated with mitochondrial dysfunction, but how these phenomena are functionally linked was not known. Understanding how these processes are regulated will be essential for developing more effective anti-cancer therapies. Here, we show that induction of mitochondrial dysfunction by either genetic or chemical approaches results in a switch from oxidative phosphorylation to glycolysis. We further show that NADPH oxidase (NOX), an enzyme known to catalyze the oxidation of NAD(P)H, also plays a critical role in supporting increased glycolysis in cancer cells by generating NAD+, a substrate for one of the key glycolytic reactions. Inhibition of NOX leads to inhibition of cancer cell proliferation in vitro and suppression of tumor growth in vivo. This study reveals a novel function for NOX in cancer metabolism, explains the increased glycolysis observed in cancer cells, and identifies NOX as a potential anti-cancer therapeutic target.

Highlights

Development of selective anticancer agents based on the biological differences between normal and cancer cells is essential to improve therapeutic selectivity
This model is based on the fact that mitochondrial DNA (mtDNA) replication is catalyzed by DNA polymerase c (POLG) and that dominant negative form of POLG (POLGdn) can abolish mtDNA replication leading to respiration defects [7,17]
Since the mitochondrial respiratory chain is a major site of cellular reactive oxygen species (ROS) generation, we examined if induction of mitochondrial dysfunction by POLGdn could lead to a change in cellular ROS

Summary

Introduction

Development of selective anticancer agents based on the biological differences between normal and cancer cells is essential to improve therapeutic selectivity. Increased aerobic glycolysis and elevated oxidative stress are two prominent biochemical features frequently observed in cancer cells. It is recognized that elevated glycolysis is a characteristic metabolism in many cancer cells. Cancer cells exhibit elevated generation of reactive oxygen species (ROS), which disturb redox balance leading to oxidative stress [2]. Despite these long-standing observations and clinical relevance, the biochemical/molecular mechanisms responsible for such metabolic alterations and their relationship with mitochondrial respiratory dysfunction remain elusive. Identification of the major molecular players involved in the metabolic switch in the context of mitochondrial dysfunction in cancer cells is important for understanding the underlying mechanisms and developing more effective treatment strategies

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Results

Conclusion