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Adaptation to oxygen deprivation elucidates tumor physiology

Two new studies in the March Cell Metabolism reveal a survival mechanism by which cells adapt to oxygen starvation by ratcheting down their demand. The mechanism serves to protect against the potentially fatal production of free radicals when oxygen is scarce, one group reported. The findings may also have important implications for understanding the physiology of cancerous tumors, the researchers said, suggesting new combination treatment strategies for fighting the disease.

When the supply of oxygen from the bloodstream fails to meet demand from body tissues--as can occur in the exercising muscle, ischemic hearts, or tumors--hypoxia results, the researchers explained. Cells adapt to low oxygen conditions by activating a "program of gene-expression changes" initiated by so-called hypoxia-inducible factor-1 (HIF-1) transcription factor.

"Over a century ago, Pasteur described that hypoxic cells increase the conversion of glucose [the body's primary energy source] to lactate, an effect that to date had been primarily attributed to the activities of hypoxia-inducible transcription factors," said study author Chi Dang, from Johns Hopkins University School of Medicine. "The accompanying decrease in cellular respiration in hypoxia was thought to result passively from the paucity of the required oxygen."

The new studies rather reveal that adaptation to hypoxia depends on an active process that serves to inhibit respiration and shunt pyruvate, the lactate precursor, away from mitochondria. Mitochondria are the cells' "power plants," where food-derived molecules are converted to usable energy via respiration.

"It is a very elegant mechanism," said study author Nicholas Denko of Stanford University School of Medicine. "The cell simply turns off the spigot that sends fuel to the mitochondria."

Both studies found that cells repress mitochondria function and oxygen consumption under low oxygen conditions through the enzyme pyruvate dehyd
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Contact: Heidi Hardman
hhardman@cell.com
617-397-2879
Cell Press
7-Mar-2006


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