Proline oxidase functions as a mitochondrial tumor suppressor in human cancers.
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-1alpha signaling was impaired with POX expression due to the increased production of alpha-ketoglutarate, a critical substrate for prolyl hydroxylation and degradation of HIF-1alpha. 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.
Liu
Yongmin
Y
Basic Science Program and Pathology/Histotechnology Laboratory, Science Applications International Corporation-Frederick, Inc., and Laboratory of Comparative Carcinogenesis, Center for Cancer Research, National Cancer Institute, Frederick, Maryland 21702, USA.
Borchert
Gregory L
GL
Donald
Steven P
SP
Diwan
Bhalchandra A
BA
Anver
Miriam
M
Phang
James M
JM
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008928:Mitochondria / Q000201:enzymology* / Q000378:metabolism / Q000502:physiology; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D011394:Proline Oxidase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D023041:Xenograft Model Antitumor Assays
D000903:Antibiotics, Antineoplastic; D025521:Tumor Suppressor Proteins; D004317:Doxorubicin; D011394:Proline Oxidase