Tumor and Stem Cell Biology Proline Oxidase Promotes Tumor Cell Survival in Hypoxic Tumor Microenvironments

Proline is a readily released stress substrate that can bemetabolized 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 prolinemetabolism to tumorigenesis in hypoxicmicroenvironments 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 AMPactivated protein kinase activation butwas independent of HIF-1a andHIF-2a. Under low-glucose and combined low-glucose and hypoxic conditions, proline catabolized by POX was used preferentially for ATP production, whereas under hypoxia, POXmediated autophagic signaling for survival by generating ROS. Although the specific mechanismwas 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. Cancer Res; 72(14); 1–10. 2012 AACR.