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Carcinogenesis Advance Access published online on February 6, 2008
Carcinogenesis, doi:10.1093/carcin/bgn028
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© The Author 2008. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Plasminogen Activator Inhibitor-1 (Pai-1) Blockers Suppress Intestinal Polyp Formation in Min Mice

Michihiro Mutoh1, Naoko Niho1, Masami Komiya1, Mami Takahashi1, Rina Ohtsubo1, Kiyoshi Nakatogawa2, Kentaro Ueda2, Takashi Sugimura1 and Keiji Wakabayashi1

1 Cancer Prevention Basic Research Project, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
2 Shizuoka Coffein Co.LTD., 129 Suido-cho, Shizuoka-shi, 420-0008,Japan

Request for reprints: Michihiro Mutoh, Phone 3-3542-2511;Fax 3-3542-9305; E-mail: mimutoh{at}gan2.ncc.go.jp

Obesity and hyperlipidemia are known to increase colorectal tumor risk. We noticed that Min mice, featuring a defect in the Apc-gene, develop intestinal polyps along with high serum triglyceride (TG) levels up to 10-fold those observed in wild-type mice. In these mice, mRNA expression of lipoprotein lipase, which catalyzes hydrolysis of TG, is down-regulated. In the present study, we focused on adipocytokines, especially plasminogen activator inhibitor-1 (Pai-1), which is involved in hyperlipidemic status and may promote intestinal polyp formation in Min mice. Serum Pai-1 levels in 15 week-old male Min mice were 8 times higher than in wild-type mice and hepatic Pai-1 mRNA levels were 11-fold increased. In addition, Pai-1 immunostaining was strong in small intestinal epithelial cells of Min mice. Administration of a PAI-1 inhibitor, SK-216, at 25, 50 and 100 ppm doses in the diet for 9 weeks reduced serum Pai-1 levels and hepatic Pai-1 mRNA levels of Min mice to the wild-type levels. Moreover, SK-216 at 50 and 100 ppm significantly reduced total numbers of intestinal polyps to 64 and 56% of the untreated group value, respectively. Serum TG levels were also decreased by 43% at the dose of 100 ppm. Administration of 50 ppm SK-116, another PAI-1 inhibitor, for 9 weeks similarly reduced serum Pai-1 levels, and total numbers of intestinal polyps to 70% of the untreated group value. These results indicate that Pai-1 induction associated with hypertriglyceridemia may contribute to intestinal polyp formation with Apc-deficiency, and PAI-1 could thus be a novel target for colorectal chemopreventive agents.

Received August 10, 2007; revised January 23, 2008; accepted January 23, 2008.


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