title: Suppression of urokinase receptor expression by thalidomide is associated with inhibition of nuclear factor kappaB activation and subsequently suppressed ovarian cancer dissemination.
abstract: 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-beta1 (TGF-beta1)-induced uPAR mRNA and protein; (b) a nuclear factor kappaB (NF-kappaB) activation system (phosphorylation of IkappaB-alpha and degradation of IkappaB-alpha) is necessary for the TGF-beta1-induced increase in uPAR expression, because L-1-tosylamido-2-phenylethyl chloromethyl ketone, a NF-kappaB 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 microg/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 microg/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-beta1-stimulated uPAR mRNA and protein expression possibly through suppression of NF-kappaB 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.
authors.affiliation: Department of Obstetrics and Gynecology, Hamamatsu University School of Medicine, Handayama 1-20-1, Hamamatsu, Shizuoka, Japan. hirokoba@hama-med.ac.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kobayashi
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Yagyu
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Kondo
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Kurita
authors.forename: Kiyokazu
authors.initials: K
authors.lastname: Inagaki
authors.forename: Shoji
authors.initials: S
authors.lastname: Haruta
authors.forename: Ryuji
authors.initials: R
authors.lastname: Kawaguchi
authors.forename: Takashi
authors.initials: T
authors.lastname: Kitanaka
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Sakamoto
authors.forename: Yoshihiko
authors.initials: Y
authors.lastname: Yamada
authors.forename: Naohiro
authors.initials: N
authors.lastname: Kanayama
authors.forename: Toshihiko
authors.initials: T
authors.lastname: Terao
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D045744:Cell Line, Tumor; D002813:Chondrosarcoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004357:Drug Synergism; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D017239:Paclitaxel / Q000008:administration & dosage / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000235:genetics; D055293:Receptors, Urokinase Plasminogen Activator; D013792:Thalidomide / Q000008:administration & dosage / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D053773:Transforming Growth Factor beta1; D014568:Urokinase-Type Plasminogen Activator / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D016328:NF-kappa B; C524898:PLAUR protein, human; C524899:Plaur protein, mouse; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D013792:Thalidomide; D014568:Urokinase-Type Plasminogen Activator; D017239:Paclitaxel