Carcinogenesis Advance Access originally published online on April 7, 2005
Carcinogenesis 2005 26(8):1335-1342; doi:10.1093/carcin/bgi083
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Carcinogenesis vol.26 no.8 © Oxford University Press 2005; all rights reserved.
MnSOD inhibits proline oxidase-induced apoptosis in colorectal cancer cells
Received September 28, 2004; revised and accepted March 25, 2005
1 Metabolism and Cancer Susceptibility Section, Laboratory for Comparative Carcinogenesis, National Cancer Institute, Frederick, MD 21702, USA, 2 Basic Research Program, SAIC-Frederick, Inc., Frederick, MD 21702, USA, 3 Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA and 4 Free Radical and Radiation Biology Program, Department of Radiation Oncology, University of Iowa, Iowa City, IA 52242, USA
* To whom correspondence should be addressed at: National Cancer Institute, Building 538, Room 144, Frederick, MD 21702, USA. Tel: +1 301 846 5367; Fax: +1 301 846 6093; Email: phang{at}ncifcrf.gov
Proline oxidase (POX), localized on inner mitochondrial membranes, is encoded by a p53-induced gene and metabolically participates in p53-induced apoptosis. Previously, we showed that POX catalyzed the generation of reactive oxygen species (ROS). We and others have demonstrated that overexpression of POX, independent of p53, causes apoptotic cell death in a variety of cancer cells. But a necessary role for ROS remains uncertain. Therefore, we asked whether superoxide dismutases (SOD) and catalase (CAT), important antioxidant enzymes, might interfere with the POX-dependent induction of apoptosis. In this study, we used DLD-1 colorectal cancer cells stably transfected with the POX gene under the control of a tetracycline-inducible promoter. When doxycycline was removed from the culture medium and the expression of POX was induced, apoptotic cell death was initiated. To examine the importance of the ROS-dependent component of the pathway, we infected DLD-1 POX cells with recombinant adenoviruses containing MnSOD, CuZnSOD, CAT or varying combinations of these adenoviruses followed by induced expression of POX. The expression of MnSOD inhibited POX-induced apoptosis, but others did not. Mechanistically, mitochondria-localized MnSOD dramatically reduced the release of cytochrome c to cytosol by POX. Compared with control cells, MnSOD-expressing DLD-1 POX cells generated a higher concentration of H2O2 owing to dismutation of superoxide radicals, which was elevated by POX. Thus, these data further suggest that the generation of superoxide radicals plays a crucial role in POX-induced apoptosis and the process is partially blocked by MnSOD.
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