The metabolism of proline, a stress substrate, modulates carcinogenic pathways

Amino Acids. 2008 Nov;35(4):681-90. doi: 10.1007/s00726-008-0063-4. Epub 2008 Apr 10.


The resurgence of interest in tumor metabolism has led investigators to emphasize the metabolism of proline as a "stress substrate" and to suggest this pathway as a potential anti-tumor target. Proline oxidase, a.k.a. proline dehydrogenase (POX/PRODH), catalyzes the first step in proline degradation and uses proline to generate ATP for survival or reactive oxygen species for programmed cell death. POX/PRODH is induced by p53 under genotoxic stress and initiates apoptosis by both mitochondrial and death receptor pathways. Furthermore, POX/PRODH is induced by PPARgamma and its pharmacologic ligands, the thiazolidinediones. The anti-tumor effects of PPARgamma may be critically dependent on POX/PRODH. In addition, it is upregulated by nutrient stress through the mTOR pathway to maintain ATP levels. We propose that proline is made available as a stress substrate by the degradation of collagen in the microenvironmental extracellular matrix by matrix metalloproteinases. In a manner analogous to autophagy, this proline-dependent process for bioenergetics from collagen in extracellular matrix can be designated "ecophagy".

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Review

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Apoptosis*
  • Autophagy
  • Catalysis
  • Gene Expression Regulation, Enzymologic*
  • Ligands
  • Models, Biological
  • Neoplasms / metabolism*
  • PPAR delta / metabolism
  • Proline / metabolism*
  • Proline Oxidase / metabolism
  • Protein Kinases / metabolism
  • TOR Serine-Threonine Kinases
  • Thiazolidinediones / metabolism
  • Tumor Suppressor Protein p53 / metabolism


  • Ligands
  • PPAR delta
  • Thiazolidinediones
  • Tumor Suppressor Protein p53
  • Adenosine Triphosphate
  • Proline
  • Proline Oxidase
  • Protein Kinases
  • TOR Serine-Threonine Kinases