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Proline Oxidase Functions as a Mitochondrial Tumor Suppressor in Human Cancers

¹ Basic Science Program and ² Pathology/Histotechnology Laboratory, Science Applications International Corporation-Frederick, Inc., and ³ Laboratory of Comparative Carcinogenesis, Center for Cancer Research, National Cancer Institute, Frederick, Maryland

Requests for reprints: Yongmin Liu, Basic Science Program, Science Applications International Corporation-Frederick, Inc., Frederick and National Cancer Institute at Frederick, Frederick, MD 21702. Phone: 301-846-5370; Fax: 301-402-0153; E-mail: yongminl{at}mail.nih.gov or James Phang, Laboratory of Comparative Carcinogenesis, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702. Phone: 301-846-5367; E-mail: phang{at}ncifcrf.gov.

Key Words: proline oxidase • tumor suppressor • hypoxia inducible factor • mouse model • metabolism

Tumor metabolism and bioenergetics have become important topics for cancer research and are promising targets for anticancer therapy. Although glucose serves as the main source of energy, proline, an alternative substrate, is important, especially during nutrient stress. Proline oxidase (POX), catalyzing the first step in proline catabolism, is induced by p53 and can regulate cell survival as well as mediate programmed cell death. In a mouse xenograft tumor model, we found that POX greatly reduced tumor formation by causing G₂ cell cycle arrest. Furthermore, immunohistochemical staining showed decreased POX expression in tumor tissues. Importantly, HIF-1 signaling was impaired with POX expression due to the increased production of -ketoglutarate, a critical substrate for prolyl hydroxylation and degradation of HIF-1. Combined with previous in vitro findings and reported clinical genetic associations, these new findings lead us to propose POX as a mitochondrial tumor suppressor and a potential target for cancer therapy. [Cancer Res 2009;69(16):6414–22]