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

We describe a novel unbiased screen for genetic loss that increased tumor cell growth in vivo

Yijun Chen; Rob Cairns; Ioanna Papandreou; Albert Koong; Nicholas C. Denko

2009

Scholarcy 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. He found that normal tissues used mitochondrial oxidation to account for 90% of ATP production with glycolysis accounting for 10%
  • We found that knockdown of either mitochondrial ribosomal protein L12 or cytochrome oxidase subunit 4 resulted in a similar increase in tumor growth in vivo
  • We found that knockdown of mitochondrial ribosomal protein L28 resulted in a commensurate reduction in the mitochondrial protein, with little effect on the nuclear-encoded protein, suggesting that the mitochondrial ribosome was compromised
  • While the MRPL28 cells grew more slowly in normoxia, they were not inhibited as the parental cells were in hypoxia. This slow growth of the knockdown cells in 21% oxygen could be due to the accumulation of toxic oxygen radical byproducts that are reduced in hypoxia
  • Because it is known that hypoxia can reduce mitochondrial function, we tested these cells after treatment with hypoxia, and found that in this environment that uncoupling protein 1 expression resulted in significantly increased oxygen consumption when compared to control cells
  • Blocking this adaptive response with DCA leads to increased oxygen consumption and reduced tumor growth

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