Amino Acids

, Volume 35, Issue 4, pp 681–690 | Cite as

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

  • James M. PhangEmail author
  • Steven P. Donald
  • Jui Pandhare
  • Yongmin Liu
Review Article


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 PPARγ and its pharmacologic ligands, the thiazolidinediones. The anti-tumor effects of PPARγ 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”.


Proline oxidase Proline dehydrogenase mTOR PPARγ Apoptosis Bioenergetics 



Mammalian target of rapamycin


Nuclear factor of activated T-cells


Δ1-Pyrroline-5-carboxylic acid


Proline oxidase


Peroxisome proliferator-activated receptor gamma


Proline dehydrogenase


Reactive oxygen species





This research is supported by the Intramural Research Program of the NIH, National Cancer Institute, Center for Cancer Research. This project also has been funded in part with Federal funds from the National Cancer Institute, National Institutes of Health under Contract No. N01-CO-12400.


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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • James M. Phang
    • 1
    Email author
  • Steven P. Donald
    • 1
  • Jui Pandhare
    • 1
  • Yongmin Liu
    • 2
  1. 1.Laboratory of Comparative Carcinogenesis, Center for Cancer ResearchFrederickUSA
  2. 2.Basic Research Program, SAIC-FrederickFrederickUSA

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