prline-rich endogenous antimicrobial peptide suppresses colon carcinoma cell proliferation by adaptor molecule competition

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PR-39, which is an endogenous antimicrobial peptide, can bind to Src homology 3 domains of the NADPH complex protein p47phox and the signaling adapter protein p130Cas. Recently, we have reported that PR-39, gene transduction altered invasive activity and actin structure on human hepatocellular carcinoma cells, suggesting that this peptide affects cellular signaling pathway due to its proline-rich motif. In order to clarify the mechanism of the PR-39 functions, we transfected with PR-39 gene into mouse NIH3T3 cells which were already transformed with human activated k-ras gene. The PR-39 gene transfectant showed a reorganization of actin structure and suppression of cell proliferation both in vitro and in vivo. Co-immunoprecipitation analysis revealed that the PR-39 binds to PI3-kinase p85a, which is a regulatory subunit of PI3-kinase and one of the effectors by which ras induces cytoskeletal changes and stimulates the mitogenesis. PI3-kinase activity of the PR-39 gene transfectant was decreased compared with that of the ras transformant. These results suggest that the PR-39 alters actin structure and cell proliferation rate by binding to PI3-kinase p85a and suppressing the PI3-kinase activity, The PR-39 gene transfectant derived from colon carcinoma cells also showed the morphological change and the suppression of the proliferation in vitro and vivo, suggesting that PR-39 might be a candidate for the targeting therapy of cancers.