title: Involvement of plasmin-mediated extracellular activation of progalanin in angiogenesis.
abstract: Progalanin is released from the small cell lung carcinoma line SBC-3A and converted to its active form by plasmin. To elucidate the role of progalanin activation in the extracellular compartment, matrix metalloproteinase (MMP) activity was studied in SBC-3A cells treated with progalanin siRNA, and angiogenesis was measured in tumor tissue originating from SBC-3A cell transplantation into mice. Progalanin siRNA caused downregulation of progalanin expression for approximately 8 days. MMP activity and angiogenesis were reduced in tumors induced by transplantation of progalanin siRNA-treated SBC-3A cells. In contrast, MMP-9 and MMP-2 activity and angiogenesis increased in tumors originating from progalanin siRNA-treated SBC-3A cells in the presence of galanin and progalanin. Furthermore, injection of tranexamic acid, a plasmin inhibitor, more markedly reduced MMP-9 and MMP-2 activity and angiogenesis in tumors originating from progalanin siRNA-treated SBC-3A cells and in tumor tissue originating from progalanin siRNA-treated SBC-3A cells in the presence of progalanin. The reduction of MMP-9 and MMP-2 activity with tranexamic acid was restored by galanin, but not by progalanin. Moreover, tranexamic acid reduced angiogenesis in control siRNA-treated SBC-3A cells. These results suggest that the activation of progalanin by plasmin in the extracellular compartment was involved in MMP-9 and MMP-2 activation and in angiogenesis in tumor tissue.
authors.affiliation: Laboratory of Bioorganic Chemistry, School of Pharmaceutical Sciences, University of Shizuoka, 52-1 Yada, Suruga-Ku, Shizuoka 422-8526, Japan. yamahiro@u-shizuoka-ken.ac.jp
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamamoto
authors.forename: Rina
authors.initials: R
authors.lastname: Okada
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Iguchi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ohno
authors.forename: Takashi
authors.initials: T
authors.lastname: Yokogawa
authors.forename: Kazuya
authors.initials: K
authors.lastname: Nishikawa
authors.forename: Keiko
authors.initials: K
authors.lastname: Unno
authors.forename: Minoru
authors.initials: M
authors.lastname: Hoshino
authors.forename: Atsushi
authors.initials: A
authors.lastname: Takeda
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005341:Fibrinolysin / Q000378:metabolism; D019004:Galanin / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats; D055752:Small Cell Lung Carcinoma / Q000098:blood supply*
chemical_list: D034741:RNA, Small Interfering; D019004:Galanin; D005341:Fibrinolysin; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9