KOHGO Yutaka Asahikawa Medical College, Department of Medicine, Professor, 医学部, 教授 (10133183)
OHTAKE Takaaki Asahikawa Medical College, Department of Medicine, Instructor, 医学部, 助手 (10359490)
渡 二郎 旭川医科大学, 医学部, 助手 (10311531)
|Budget Amount *help
¥3,800,000 (Direct Cost : ¥3,800,000)
Fiscal Year 2004 : ¥500,000 (Direct Cost : ¥500,000)
Fiscal Year 2003 : ¥800,000 (Direct Cost : ¥800,000)
Fiscal Year 2002 : ¥2,500,000 (Direct Cost : ¥2,500,000)
PR-39 is a mammalian endogenous antibiotic, which works as the effecter molecule of innate immunity, induces the synthesis of syndecan-1, a transmembrane heparin sulphate proteoglycan involved in cell-to matrix interactions and skin wound healing. Previously we revealed that the expression of syndecan-1 was reduced in human hepatocellular carcinomas with high metastatic potential (Matsumoto, Int J Cancer,1997). Gene transduction of syndecan-1 inhibits the invasion activity in hepatoma cell lines. Furthermore gene transduction of PR-39, which is inducer for syndecan-1, inhibits the invasion activity and suppresses the motile activity in addition to the disorganization of action structure (Ohtake, Br J Cancer,1999).
PR-39 has five repeats of the praline-rich motif ; PXXPPXXP, which has an ability to bind to Src homology 3 (SH3) domains. PR-39 actually binds to SH3 domains of p47^<phox> and p130^<Cas>. To determine the target molecule of PR-39 in intracellular signal transduction pathway,
we transfected PR-39 gene into the fibroblasts which had already been transformed with activated k-ras. The PR-39 gene transfectant showed reorganization of actin structure, suppression of cell proliferation and decrease of mitogen-activated protein (MAP) kinase activity PR-39 binds to PI3-kinase p85α, which is a regulatory subunit of PI3-kinase and one of the effectors by which ras induces cytoskeletal changes and stimulates mitogenesis. So our data suggest that PR-39 alters actin structure and cell proliferation by binding to PI3-kinase p85α (Tanaka, Jpn J Cancer Res,2001).
Furthermore, we investigated with anti-cancer effect of PR-39 against mouse colon cancer cell line, colo26, which revealed cachexia using the mouse model of subcutaneous tumor transplantation. There was no effect for suppression of tumor growth in both the mice which have intra-pentoneal load of synthetic peptide of PR-39, and PR-39 transgenic mice, which were subcutaneously transplanted with colo26. Either not in the mice which were subcutaneously transplanted with colo26, which had been transfected with PR-39. However, the survival period of only the mice which carried PR-39 transfectants extended as compared with the control. Our data suggest that PR-39 gene transduction may improve cachexia and extend survival period. Less