Proline dehydrogenase (oxidase), a mitochondrial tumor suppressor, and autophagy under the hypoxia microenvironment

Autophagy. 2012 Sep;8(9):1407-9. doi: 10.4161/auto.21152. Epub 2012 Aug 13.


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.

MeSH terms

  • Animals
  • Autophagy*
  • Cell Hypoxia
  • Cellular Microenvironment*
  • Glucose / deficiency
  • Humans
  • Mice
  • Mitochondria / enzymology*
  • Models, Biological
  • Proline Oxidase / metabolism*
  • Reactive Oxygen Species / metabolism
  • Tumor Suppressor Proteins / metabolism*
  • Xenograft Model Antitumor Assays


  • Reactive Oxygen Species
  • Tumor Suppressor Proteins
  • Proline Oxidase
  • Glucose