Many solid
tumors consist of large regions of poorly perfused cells, resulting in areas of low
oxygen (
hypoxia) throughout the cell mass. Cells subjected to
hypoxia turn on a complex set of responses that alter their metabolism, rebalance their survival mechanisms, increase their invasive capacity, and stimulate angiogenesis. This allows them to at least temporarily escape the nutrient
starvation and cell death resulting from this hostile environment. Accordingly, the hypoxic regions of
tumors are often sources of the most aggressive and
therapy-resistant cells, and therefore those cells that drive
tumorigenesis. The
hypoxia inducible factor (HIF)
prolyl hydroxylases (PHDs) are
enzymes that are functionally inactivated in
hypoxia, as they use both
oxygen and
alpha-ketoglutarate as substrates to hydroxylate target prolyl residues. Although HIF1alpha, the most highly characterized PHD target, orchestrates many of the cellular responses to
hypoxia observed in
tumors, PHDs themselves have previously been shown to regulate some
hypoxia responses, including apoptosis, in a HIF-independent mechanism. We have previously shown that PHDs can be reactivated under
hypoxia and that this results in a metabolic defect, both in vitro and in vivo. This led us to investigate whether chronic reactivation of these
enzymes may inhibit
tumor progression. We show here that esterified
alpha-ketoglutarate given daily will induce apoptosis and inhibit
tumor growth, in vivo. The effects are independent of HIF1alpha but dependent on the presence of PHD3. These data suggest that PHD3 may be a valid target in vivo for anti-
tumor therapy.