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Suppression of Urokinase Receptor Expression by Thalidomide Is Associated with Inhibition of Nuclear Factor B Activation and Subsequently Suppressed Ovarian Cancer Dissemination

¹ Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, Handayama, Hamamatsu, Shizuoka; ² NetForce Co. Ltd., Taiko, Nakamura; ³ Computer Technology Integration, Co. Ltd., Meieki-minami, Nakamura, Nagoya, Aichi; ⁴ Department of Knowledge-Based Information Engineering, Toyohashi University of Technology, Tempaku-cho, Toyohashi; and ⁵ Department of Obstetrics and Gynecology, Nara Medical University, Shijo-cho, Kashihara, Nara, Japan

Requests for reprints: Hiroshi Kobayashi, Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, Handayama 1-20-1, Hamamatsu, Shizuoka 431-3192, Japan. Phone: 81-53-435-2309; Fax: 81-53-435-2308; E-mail: hirokoba{at}hama-med.ac.jp.

Thalidomide has been used to treat a variety of diseases ranging from alleviation of autoimmune disorders to prevention of metastasis of cancers. It has been shown previously that increased levels of urokinase-type plasminogen activator receptor (uPAR) correlate well with higher invasive phenotype. We examined whether thalidomide is able to suppress the expression of uPAR mRNA and protein in human ovarian cancer cell line HRA and human chondrosarcoma cell line HCS-2/8. Here, we show that: (a) thalidomide suppresses the expression of constitutive and transforming growth factor-ß1 (TGF-ß1)–induced uPAR mRNA and protein; (b) a nuclear factor B (NF-B) activation system (phosphorylation of IB- and degradation of IB-) is necessary for the TGF-ß1-induced increase in uPAR expression, because L-1-tosylamido-2-phenylethyl chloromethyl ketone, a NF-B inhibitor, reduced the uPAR production as well as mRNA expression; (c) thalidomide failed to further strengthen L-1-tosylamido-2-phenylethyl chloromethyl ketone's action; (d) the once-daily i.p. administration of thalidomide (400 µg/g body weight/d) decreased progressive growth of HRA tumors and ascites formation in an in vivo animal model; and (e) the once-daily i.p. administration of thalidomide in combination with paclitaxel (i.p., 100 µg/20 g at days 2 and 5) significantly decreased progressive growth of HRA cells in a synergistic fashion. We conclude that thalidomide down-regulates constitutive and TGF-ß1-stimulated uPAR mRNA and protein expression possibly through suppression of NF-B activation. Furthermore, combination therapy with thalidomide plus paclitaxel may be an effective way to markedly reduce i.p. tumor growth and ascites in ovarian cancer dissemination.