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."
The researchers include Jung-whan Kim, Irina Tchernyshyov, Gregg L. Semenza, and Chi V. Dang of the Johns Hopkins University School of Medicine in Baltimore, Maryland; Ioanna Papandreou, Rob A. Cairns, Lucrezia Fontana, Ai Lin Lim, and Nicholas C. Denko of Stanford University School of Medicine in Stanford, California.
This work was supported by National Institutes of Health (NIH)/National Cancer Institute (NCI) grants CA52497, CA57341, and NHLBI NO1-HV-28180; grant CA67166 from the National Cancer Institute (NCI); J.-W.K. is a Howard Hughes Medical Institute Predoctoral Fellow. C.V.D. is a Johns Hopkins Family Professor in Oncology Research. These findings were first presented at the NCI Workshop ''Mitochondrial Function and Cancer'' in May 2004 (Perry et al., 2004).
Kim et al.: "HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia." Publishing in Cell Metabolism Vol. 3, 177–185, March 2006. DOI 10.1016/j.cmet.2006.02.002 www.cellmetabolism.org
Papandreou et al.: "HIF-1 mediates adaptation to hypoxia by actively downregulating mitochondrial oxygen consumption." Publishing in Cell Metabolism Vol. 3, 187-197, March 2006. DOI 10.1016/j.cmet.2006.01.012 www.cellmetabolism.org
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