title: Protein C inhibitor inhibits breast cancer cell growth, metastasis and angiogenesis independently of its protease inhibitory activity.
abstract: Protein C inhibitor (PCI) regulates the anticoagulant protein C pathway and also inhibits urinary plasminogen activator (uPA), a mediator of tumor cell invasion. In the present study, we evaluated the effect of human PCI and its inactive derivatives on tumor growth and metastasis of human breast cancer (MDA-231) cells, and on angiogenesis in vivo. The invasiveness of MDA-231 cells was inhibited by recombinant intact PCI, but not by reactive site-modified PCI (R354APCI) or by the N-terminal fragment of protease-cleaved PCI (NTPCI). The in vitro invasiveness of MDA-231 cells expressing intact PCI (MDA-PCI) was significantly decreased as compared to MDA-231 cells expressing R354APCI (MDA-R354APCI) or NTPCI (MDA-NTPCI). Further, in vivo growth and metastatic potential of MDA-PCI, MDA-R354APCI and MDA-NTPCI cells in severe combined immunodeficient (SCID) mice were significantly decreased as compared to MDA-Mock cells. Angiogenesis was also significantly decreased in Matrigel implant containing MDA-PCI, MDA-R354APCI or MDA-NTPCI cells as compared to that containing MDA-Mock cells. In vivo angiogenesis in rat cornea and in vitro tube formation were also inhibited by recombinant intact PCI, R354APCI and NTPCI. Furthermore, the anti-angiogenic activity of PCI was strong as cleaved antithrombin (AT), and slightly stronger than that of plasminogen activator inhibitor (PAI)-1 and pigment epithelium-derived factor (PEDF). Overall, this study showed that, in addition to a reactive site-dependent mechanism, PCI may also regulate tumor growth and metastasis independently of its protease inhibitory activity by inhibiting angiogenesis.
authors: Department of Molecular Pathobiology, Mie University Graduate School of Medicine, Tsu-city, Mie, Japan.
authors: Kunihiro
authors: K
authors: Asanuma
authors: Tomoaki
authors: T
authors: Yoshikawa
authors: Tatsuya
authors: T
authors: Hayashi
authors: Nobuyuki
authors: N
authors: Akita
authors: Norimi
authors: N
authors: Nakagawa
authors: Yasuhiko
authors: Y
authors: Hamada
authors: Junji
authors: J
authors: Nishioka
authors: Haruhiko
authors: H
authors: Kamada
authors: Esteban C
authors: EC
authors: Gabazza
authors: Masaru
authors: M
authors: Ido
authors: Atsumasa
authors: A
authors: Uchida
authors: Koji
authors: K
authors: Suzuki
mesh_terms: D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000098:blood supply / Q000473:pathology*; D002455:Cell Division / Q000502:physiology*; D045744:Cell Line, Tumor; D017931:DNA Primers; D004591:Electrophoresis, Polyacrylamide Gel; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic; D018046:Protein C Inhibitor / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D018046:Protein C Inhibitor