A Novel Function for Hydroxyproline Oxidase in Apoptosis through Generation of Reactive Oxygen Species

Proline and hydroxyproline are metabolized by distinct pathways. Proline is important for protein synthesis, as a source of glutamate, arginine, and tricarboxylic acid cycle intermediates, and for participating in a metabolic cycle that shuttles redox equivalents between mitochondria and cytosol. Hy...

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Bibliographic Details
Published in:	The Journal of biological chemistry Vol. 283; no. 16; pp. 10485 - 10492
Main Authors:	Cooper, Sandra K., Pandhare, Jui, Donald, Steven P., Phang, James M.
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 18-04-2008 American Society for Biochemistry and Molecular Biology
Subjects:	Apoptosis Caspase 9 - metabolism Cell Line Cell Line, Tumor Doxorubicin - pharmacology Enzyme Activation Gene Expression Regulation Humans Metabolism and Bioenergetics Models, Biological Models, Chemical Oxidoreductases Acting on CH-NH Group Donors - chemistry Oxidoreductases Acting on CH-NH Group Donors - physiology Proline Oxidase - metabolism Reactive Oxygen Species Tumor Suppressor Protein p53 - metabolism
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Summary:	Proline and hydroxyproline are metabolized by distinct pathways. Proline is important for protein synthesis, as a source of glutamate, arginine, and tricarboxylic acid cycle intermediates, and for participating in a metabolic cycle that shuttles redox equivalents between mitochondria and cytosol. Hydroxyproline, in contrast, is not reutilized for protein synthesis. The first steps in the degradation of proline and hydroxyproline are catalyzed by proline oxidase (POX) and hydroxyproline oxidase (OH-POX), respectively. Because it is well documented that POX is induced by p53 and plays a role in apoptosis, we considered whether OH-POX also participates in the response to cytotoxic stress. In LoVo and RKO cells, which respond to adriamycin with a p53-mediated induction of POX and generation of reactive oxygen species, we found that adriamycin also induced OH-POX gene expression and markedly increased OH-POX catalytic activity, and this increase in activity was not observed in the cell lines HT29 and HCT15, which do not have a functional p53. We also observed an increase in reactive oxygen species generation and activation of caspase-9 with adriamycin in a hydroxyproline-dependent manner. Therefore, we hypothesize that OH-POX plays a role analogous to POX in growth regulation, ROS generation, and activation of the apoptotic cascade.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Both authors contributed equally to this work. To whom correspondence should be addressed: NCI Frederick, National Institutes of Health, Laboratory of Comparative Carcinogenesis, Bldg.538, Rm. No. 144, Frederick, MD 21702. Tel.: 301-846-5367; Fax: 301-846-6093; E-mail: phang@ncifcrf.gov. This work was supported by federal funds from the NCI, National Institutes of Health, under contract N01-CO-12400 and by a grant from the Intramural Research Program of the National Institutes of Health, NCI, Center for Cancer Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
ISSN:	0021-9258 1083-351X
DOI:	10.1074/jbc.M702181200