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J. Biol. Chem., Vol. 278, Issue 21, 19396-19405, May 23, 2003

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Potential Role of Microsomal Prostaglandin E Synthase-1 in Tumorigenesis^*

Daisuke Kamei , Makoto Murakami , Yoshihito Nakatani , 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, Japan, Department of Pathology, Toho University, School of Medicine, 5-21-16 Omori-Nishi, Ohta-ku, Tokyo 143-8540, Japan

Microsomal prostaglandin E₂ synthase-1 (mPGES-1) is a stimulus-inducible enzyme that functions downstream of cyclooxygenase (COX)-2 in the PGE₂-biosynthetic pathway. Given the accumulating evidence that COX-2-derived PGE₂ participates in the development of various tumors, including colorectal cancer, we herein examined the potential involvement of mPGES-1 in tumorigenesis. Immunohistochemical analyses demonstrated the expression of both COX-2 and mPGES-1 in human colon cancer tissues. HCA-7, a human colorectal adenocarcinoma cell line that displays COX-2- and PGE₂-dependent proliferation, expressed both COX-2 and mPGES-1 constitutively. Treatment of HCA-7 cells with an mPGES-1 inhibitor or antisense oligonucleotide attenuated, whereas overexpression of mPGES-1 accelerated, PGE₂ production and cell proliferation. Moreover, cotransfection of COX-2 and mPGES-1 into HEK293 cells resulted in cellular transformation manifested by colony formation in soft agar culture and tumor formation when implanted subcutaneously into nude mice. cDNA array analyses revealed that this mPGES-1-directed cellular transformation was accompanied by changes in the expression of a variety of genes related to proliferation, morphology, adhesion, and the cell cycle. These results collectively suggest that aberrant expression of mPGES-1 in combination with COX-2 can contribute to tumorigenesis.

Received for publication, December 31, 2002 , and in revised form, February 25, 2003.

^¶ To whom correspondence should be addressed. Tel.: 81-3-3784-8196; Fax: 81-3-3784-8245; E-mail: kudo{at}pharm.showa-u.ac.jp.

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