title: Proline dehydrogenase (oxidase), a mitochondrial tumor suppressor, and autophagy under the hypoxia microenvironment.
abstract: Proline dehydrogenase (oxidase, PRODH/POX), the first enzyme in the pathway of proline catabolism, has been identified as a mitochondrial, metabolic tumor suppressor, which is downregulated in a variety of human tumors. However, our recent findings show that PRODH/POX is upregulated by hypoxia in vitro and in vivo. The combination of low glucose and hypoxia produces additive effects on PRODH/POX expression. Both hypoxia and glucose depletion enhance PRODH/POX expression through AMP-activated protein kinase (AMPK) activation to promote tumor cell survival. Nevertheless, the mechanisms underlying PRODH/POX prosurvival functions are different for hypoxia and low-glucose conditions. Glucose depletion with or without hypoxia elevates PRODH/POX and proline utilization to supply ATP for cellular energy needs. Interestingly, under hypoxia PRODH/POX induces protective autophagy by generating reactive oxygen species (ROS). AMPK is the main initiator of stress-triggered autophagy. Thus, PRODH/POX acts as a downstream effector of AMPK in the activation of autophagy under hypoxia. This regulation was confirmed to be independent of the mechanistic target of rapamycin (MTOR) pathway, a major downstream target of AMPK signaling.
authors.affiliation: Metabolism and Cancer Susceptibility Section, Basic Research Laboratory, Center for Cancer Research, Frederick National Laboratory for Cancer Research, National Institutes of Health, Frederick, MD, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: James M
authors.initials: JM
authors.lastname: Phang
mesh_terms: D000818:Animals; D001343:Autophagy; D015687:Cell Hypoxia; D060833:Cellular Microenvironment; D005947:Glucose / Q000172:deficiency; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000201:enzymology*; D008954:Models, Biological; D011394:Proline Oxidase / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D017382:Reactive Oxygen Species; D025521:Tumor Suppressor Proteins; D011394:Proline Oxidase; D005947:Glucose