Proline oxidase plays a tumor suppressor role in human cancer Free

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Proline oxidase (POX), localized in the inner mitochondrial membrane, catalyzes the conversion of proline to pyrroline-5-carboxylate. Together with pyrroline-5-carboxylate reductase, POX mediates the proline cycle to shuttle redox equivalents between mitochondria and cytosol. POX is elevated during p53-induced apoptosis and may regulate cell survival in situations of nutritional and energetic stress. We have shown that POX generated proline-dependent reactive oxygen species (ROS), specifically superoxide radicals, and induced apoptosis through both mitochondrial and death receptor pathways. To further determine the role of POX in growth inhibition in vivo, we developed a xenograft tumor model using DLD-1 Tet-off POX cells. Athymic mice were randomized to receive drinking water with or without doxycycline. The development of tumors was greatly reduced/delayed in the group without doxycycline. For those mice without tumors in the group without DOX, half were switched to water with DOX. The delayed development of tumors with POX expression (without DOX) continued to be observed. Immunohistochemical staining of tumor tissue showed no difference in TUNEL staining between (+) DOX and (-) DOX tumors, but BrdU staining was lower in the (-) DOX group. Consistent with this, cell cycle studies showed that % of cells in G2 arrest increased with decreasing DOX concentration. Importantly, immunohistochenmical staining of a variety of human tumors and their corresponding normal tissues demonstrated decreased POX expression in tumor tissues, especially in tumors of colon, stomach, liver, pancreas and kidney. Taken together, these data led us to propose POX as a candidate tumor suppressor and a potential target for activation in cancer prevention and treatment.