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

Yijun Chen,Albert Koong,Nicholas C Denko,Rob Cairns,Ioanna Papandreou,Mikhail V Blagosklonny

doi:10.1371/journal.pone.0007033

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.

Highlights

Otto Warburg won the Nobel Prize for physiology or medicine in 1931, and we are still working to understand the significance of his discoveries
We 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
Using his newly developed techniques, he characterized the energy production within solid tumors and compared it to that in normal tissue [1]. He found that normal tissues used mitochondrial oxidation to account for 90% of ATP production with glycolysis accounting for 10%

Summary

Introduction

Otto Warburg won the Nobel Prize for physiology or medicine in 1931, and we are still working to understand the significance of his discoveries. His work on oxidation and reduction and energy production is essential for our current understanding of intermediate metabolism. Using his newly developed techniques, he characterized the energy production within solid tumors and compared it to that in normal tissue [1]. Tumors used less of the highly efficient oxidative phosphorylation, producing 50% of the ATP from oxidation and 50% from glycolysis This shift was thought to occur even though there was sufficient oxygen to support mitochondrial function and is called ‘‘aerobic glycolysis’’[1]. ‘‘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

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Conclusion