title: Proline oxidase promotes tumor cell survival in hypoxic tumor microenvironments.
abstract: 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.
authors.affiliation: Metabolism and Cancer Susceptibility Section, Basic Research Laboratory, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, USA. liuwei3@mail.nih.gov
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Kristine
authors.initials: K
authors.lastname: Glunde
authors.forename: Zaver M
authors.initials: ZM
authors.lastname: Bhujwalla
authors.forename: Venu
authors.initials: V
authors.lastname: Raman
authors.forename: Anit
authors.initials: A
authors.lastname: Sharma
authors.forename: James M
authors.initials: JM
authors.lastname: Phang
mesh_terms: D000818:Animals; D001343:Autophagy; D001943:Breast Neoplasms / Q000201:enzymology; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival; D005260:Female; D005947:Glucose / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D011392:Proline / Q000378:metabolism; D011394:Proline Oxidase / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment; D015854:Up-Regulation
chemical_list: D017382:Reactive Oxygen Species; D011392:Proline; D011394:Proline Oxidase; D005947:Glucose