Human RNASET2 Derivatives as Potential Cancer Therapeutic Agents

Human RNASET2 has been implicated in antiangiogenic and antitumorigenic activities via a mechanism associated with specific binding to actin and inhibition of the cell motility, independent of its ribonuclease capacities. We have constructed a truncated version of human RNASET2, with an incomplete RNase active site (trT2-50) which maintained its ability to bind actin, inhibit angiogenesis and consequently tumorigenesis in vitro and in vivo. We identified the region that is involved in the ability to bind actin, a 26 amino acid sequence derived from the hRNASET2 protein (peptide K108-K133). This peptide was tested for its ability to bind actin using the immobilized actin solid phase assay (ELISA) and the BIAcore system. These assays revealed that hrRNASET2, trT2-50 and peptide K108-K133 bound actin with similar affinities. We continued by demonstrating that peptide K108-K133 has the ability to inhibit angiogenesis using the in vitro HUVEC tube formation assay and the ex ovo CAM assay. Previous studies have shown that migrating cells display higher levels of actin polymerization as compared to stationary cells. We therefore suggest that endothelial and tumor cells may be sensitive to trT2-50 or peptide K108-K133 treatment. The focus of my study is to shed light on the putative mechanism of action by which the hRNASET2 associated proteins inhibit angiogenesis. In conclusion, we present the actin-binding sequence of the hRNASET2 protein. We identified a 26 amino acid short peptide that is a derivative of the hRNASET2, which is able to bind actin and consequently inhibit angiogenesis. The effect of this newly designed peptide is similar to the hrRNASET2 and trT2-50 and therefore may offer a novel antiangiogenic therapeutic agent that will prevent tumor progression.