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J. Biol. Chem., Vol. 280, Issue 36, 31428-31437, September 9, 2005

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Suppression of Urokinase Expression and Invasion by a Soybean Kunitz Trypsin Inhibitor Are Mediated through Inhibition of Src-dependent Signaling Pathways^*

From the ^aNetForce Co. Ltd., Taiko 3-1-18, Nakamura, Nagoya, Aichi 453-0801, Japan, the ^bDepartment of Obstetrics and Gynecology, Hamamatsu University School of Medicine, Handayama 1-20-1, Hamamatsu, Shizuoka 431-3192, Japan, the ^dFood Science Research Institute, Tsukuba R&D Center, Fuji Oil Co. Ltd., 4-3 Kinunodai, Yawara-mura, Tsukuba-gun, Ibaraki 300-2497, Japan, the ^eHannan R&D Center, Fuji Oil Co. Ltd., 1 Sumiyoshi-cho, Izumisano, Osaka 598-0061, Japan, the ^fComputer Technology Integration Co. Ltd., Meieki-minami 1-27-2, Nakamura, Nagoya, Aichi 450-0003, Japan, the ^gDepartment of Knowledge-based Information Engineering, Toyohashi University of Technology, Tempaku-cho, Toyohashi 441-8580, Japan, and the ^hDepartment of Obstetrics and Gynecology, Nara Medical University, 840 Shijo-cho, Kashihara, Nara 634-8522, Japan

A soybean Kunitz trypsin inhibitor (KTI) interacts with cells as a negative modulator of the invasive cells. Using complementary pharmacological and genetic approaches, we provide novel findings regarding mechanisms by which KTI inhibits signaling pathways in ovarian cancer cells leading to invasion. Transforming growth factor-1 (TGF-1) directly activates Src kinase, which in turn activates ERK-phosphatidylinositol 3-kinase/Akt, the downstream targets of Src, for urokinase-type plasminogen activator (uPA) up-regulation in human ovarian cancer HRA cells. Preincubation of the HRA cells with KTI reduced the ability of TGF-1 to trigger the uPA expression at the gene level and at the protein level. To further elucidate the mechanism of the KTI-dependent suppressive effect of TGF-1-induced uPA expression and invasion, we investigated which signaling pathway transduced by KTI is responsible for this inhibitory effect. Here, we show that 1) KTI suppressed TGF-1-induced phosphorylation of Src, ERK1/2, and Akt by 40–60%; 2) KTI was insensitive to suppress the phosphorylation of ERK1/2 and Akt in the constitutively active (CA)-c-Src (Y529F) cells; 3) uPA expression was up-regulated in TGF-1-stimulated HRA cells and in unstimulated Y529F cells; 4) the addition of KTI reduced the TGF-1-induced increase of uPA gene and protein expression in the wild-type c-Src-transfected cells (in contrast, KTI could not inhibit uPA expression in the Y529F cells); and 5) CA-c-Src transfection resulted in a 2-fold increase in invasiveness, whereas KTI did not reduce invasion of the Y529F cells. Using additional complementary genetic approaches (CA-MEK1, CA-Akt, or kinase-dead-Akt), we conclude that KTI may suppress uPA expression and promotion of invasion possibly through one or more upstream targets of Src.

Received for publication, February 7, 2005 , and in revised form, July 5, 2005.

^* This work was supported by a grant-in-aid for Scientific Research from the Ministry of Education, Science and Culture of Japan (to H. K.) and by grants from the Fuji Foundation for Protein Research (to H. K.), the Kanzawa Medical Foundation (to H. K.), the Sagawa Cancer Research foundation (to H. K.), and the Aichi Cancer Research Foundation (to H. K). 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.

^c To whom correspondence should be addressed. Tel.: 81-53-435-2309; Fax: 81-53-435-2308; E-mail: hirokoba{at}hama-med.ac.jp.

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