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 dehydrogenase kinase 1 (PDK1).

Dang’s group showed that, under hypoxic conditions, mouse cells lacking HIF-1 fail to activate PDK1 and undergo cell death (apoptosis) following a dramatic rise in the level of reactive oxygen species (ROS). Forced PDK1 expression in hypoxic cells lacking HIF-1 limited toxic free radical generation and rescued the cells from hypoxia-induced death.

Denko’s team similarly demonstrated in tumor cells that HIF-1 causes a drop in oxygen use, resulting in increased oxygen availability and decreased cell death under low oxygen conditions–findings that might have important implications for cancer therapy, he said.

Indeed, his group found HIF-1 activity made cells more resistant to the antitumor drug tirapazamine (TPZ). They also found that HIF-1-deficient cells grown with limited oxygen exhibit increased sensitivity to TPZ relative to normal cells.

“Recent interest has focused on cytotoxins that target hypoxic cells in tumor microenvironments, such as the drug tirapazamine,” said Howard Hughes Medical Institute investigator M. Celeste Simon in a preview. “Because intracellular oxygen concentrations are decreased by mitochondrial oxygen consumption, HIF-1 could protect tumor cells from TPZ-mediated cell death by maintaining intracellular oxygen levels.”

While HIF-1 inhibition in hypoxic tumor cells should have multiple therapeutic benefits, Simon added, “the use of HIF-1 inhibitors in conjunction with other treatments has to be carefully evaluated for the most effective combination and sequence of drug delivery.”