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J. Biol. Chem., Vol. 280, Issue 26, 24987-24998, July 1, 2005

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Cellular Distribution, Post-translational Modification, and Tumorigenic Potential of Human Group III Secreted Phospholipase A₂^*

Makoto Murakami¶, Seiko Masuda, Satoko Shimbara, Yukio Ishikawa||, Toshiharu Ishii||, and Ichiro Kudo

From the Department of Health Chemistry, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, the Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyo-ku, Tokyo 113-8613, and the ^||Department of Pathology, Toho University, School of Medicine, 5-21-16 Omori-Nishi, Ohta-ku, Tokyo 143-8540, Japan

Human group III secreted phospholipase A₂ (sPLA₂-III) consists of a central group III sPLA₂ domain flanked by unique N- and C-terminal domains. We found that the sPLA₂ domain alone was sufficient for its catalytic activity and for its prostaglandin E₂ (PGE₂)-generating functions in various cell types. In several if not all cell types, the N- and C-terminal domains of sPLA₂-III were proteolytically removed, leading to the production of the form containing only the sPLA₂ domain, which could be further N-glycosylated at two consensus sites. Immunohistochemistry demonstrated that sPLA₂-III was preferentially expressed in the microvascular endothelium in human tissues with inflammation, ischemic injury, and cancer. In support of this, sPLA₂-III was induced in cultured microvascular endothelial cells after stimulation with proinflammatory cytokines. Expression of sPLA₂-III was also associated with various tumor cells, and colorectal cancer cells transfected with sPLA₂-III exhibited enhanced PGE₂ production and cell proliferation, which required sPLA₂-III catalytic activity. When implanted into nude mice, the sPLA₂-III-transfected cells formed larger solid tumors with increased angiogenesis compared with control cells. Moreover, small interfering RNA for sPLA₂-III significantly reduced PGE₂ production and proliferation of colorectal cancer cells. Taken together, these results reveal unique cell type-specific processing and N-glycosylation of sPLA₂-III and the potential role of this enzyme in cancer development by stimulating tumor cell growth and angiogenesis.

Received for publication, February 23, 2005 , and in revised form, April 26, 2005.

^* This work was supported by grants-in-aid for scientific research from the Ministry of Education, Science, Culture, Sports and Technology of Japan. 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.

^¶ To whom correspondence should be addressed: Dept. of Health Chemistry, School of Pharmaceutical Sciences, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8555, Japan, and the Tokyo Metropolitan Institute of Medical Science, 3-18-22 Honkomagome, Bunkyoku, Tokyo 113-8613, Japan. Tel.: 81-3-3794-8197; Fax: 81-3-3784-8245; E-mail: mako{at}pharm.showa-u.ac.jp or mako{at}rinshoken.or.jp.

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