Proline is a readily released stress substrate that can be metabolized by
proline oxidase (POX) to generate either
reactive oxygen species (ROS) to induce apoptosis or autophagy or
ATP during times of nutrient stress. However, the contribution of
proline metabolism to
tumorigenesis in hypoxic microenvironments has not been explored. In this study, we investigated the different functions of POX under
hypoxia and
glucose depletion. We found that
hypoxia induced POX expression in
cancer cells in vitro and that POX upregulation colocalized with hypoxic tissues in vivo. In addition, the combination of
hypoxia and low
glucose showed additive effects on POX expression. Similar to conditions of low
glucose,
hypoxia-mediated POX induction was dependent on
AMP-activated protein kinase activation but was independent of HIF-1α and HIF-2α. Under low-
glucose and combined low-
glucose and hypoxic conditions,
proline catabolized by POX was used preferentially for
ATP production, whereas under
hypoxia, POX mediated autophagic signaling for survival by generating ROS. Although the specific mechanism was different for
hypoxia and
glucose deprivation, POX consistently contributed to
tumor cell survival under these conditions. Together, our findings offer new insights into the metabolic reprogramming of
tumor cells present within a hostile microenvironment and suggest that
proline metabolism is a potential target for
cancer therapeutics.