The metabolism of proline, a stress substrate, modulates carcinogenic pathways.
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".
Phang
James M
JM
Laboratory of Comparative Carcinogenesis, Center for Cancer Research, Building 538, Room 115, NCI-Frederick, Frederick, MD 21702, USA. phang@mail.ncifcrf.gov
Donald
Steven P
SP
Pandhare
Jui
J
Liu
Yongmin
Y
D000255:Adenosine Triphosphate / Q000378:metabolism; D017209:Apoptosis; D001343:Autophagy; D002384:Catalysis; D015971:Gene Expression Regulation, Enzymologic; D008024:Ligands; D008954:Models, Biological; D009369:Neoplasms / Q000378:metabolism*; D047494:PPAR delta / Q000378:metabolism; D011392:Proline / Q000378:metabolism*; D011394:Proline Oxidase / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases; D045162:Thiazolidinediones / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D008024:Ligands; D047494:PPAR delta; D045162:Thiazolidinediones; D016159:Tumor Suppressor Protein p53; D000255:Adenosine Triphosphate; D011392:Proline; D011394:Proline Oxidase; D011494:Protein Kinases; D058570:TOR Serine-Threonine Kinases