Oxygen Consumption Can Regulate the Growth of Tumors, a New Perspective on the Warburg Effect

Abstract

BackgroundThe unique metabolism of tumors was described many years ago by Otto Warburg, who identified tumor cells with increased glycolysis and decreased mitochondrial activity. However, “aerobic glycolysis” generates fewer ATP per glucose molecule than mitochondrial oxidative phosphorylation, so in terms of energy production, it is unclear how increasing a less efficient process provides tumors with a growth advantage.Methods/FindingsWe carried out a screen for loss of genetic elements in pancreatic tumor cells that accelerated their growth as tumors, and identified mitochondrial ribosomal protein L28 (MRPL28). Knockdown of MRPL28 in these cells decreased mitochondrial activity, and increased glycolysis, but paradoxically, decreased cellular growth in vitro. Following Warburg's observations, this mutation causes decreased mitochondrial function, compensatory increase in glycolysis and accelerated growth in vivo. Likewise, knockdown of either mitochondrial ribosomal protein L12 (MRPL12) or cytochrome oxidase had a similar effect. Conversely, expression of the mitochondrial uncoupling protein 1 (UCP1) increased oxygen consumption and decreased tumor growth. Finally, treatment of tumor bearing animals with dichloroacetate (DCA) increased pyruvate consumption in the mitochondria, increased total oxygen consumption, increased tumor hypoxia and slowed tumor growth.ConclusionsWe interpret these findings to show that non-oncogenic genetic changes that alter mitochondrial metabolism can regulate tumor growth through modulation of the consumption of oxygen, which appears to be a rate limiting substrate for tumor proliferation.

Transforming Growth Factor β Mediates Drug Resistance by Regulating the Expression of Pyruvate Dehydrogenase Kinase 4 in Colorectal Cancer

“…Phosphorylation and inactivation of PDH by PDKs favors the glycolytic phenotype, which confers resistance to apoptosis (18,19). Inhibition of PDKs switches glucose metabolism to aerobic oxidation, which is disadvantageous to tumor growth (20).…”

Cancer as a Metabolic Disease

“…While reduced oxygen uptake can be indicative of reduced oxidative phosphorylation, increased oxygen uptake may or may not be indicative of increased oxidative phosphorylation and ATP production [59][60][61][62]. Ramanathan and co-workers showed that oxygen consumption was greater, but oxygen dependent (aerobic) ATP synthesis was less in cells with greater tumorigenic potential than in cells with lower tumorigenic potential [61].…”

“…Numerous studies show that tumor mitochondria are structurally and functionally abnormal and incapable of generating normal levels of energy [10,60,61,[68][69][70][71][72][73][74]. Recent evidence also shows that the in vitro growth environment alters the lipid composition of mitochondrial membranes and electron transport chain function [75].…”

Dichloroacetate metabolically targeted therapy defeats cytotoxicity of standard anticancer drugs

“…In preclinical in vivo studies DCA reduced the growth of non-small cell lung cancer xenografts and significantly diminished the number of lung metastasis in a rat mammary adenocarcinoma metastasis model [6,9]. In addition, reversal of the glycolytic phenotype reduced the growth of pancreas tumour xenografts [10].…”