GAP 161 targets and downregulates G 3 BP to suppress cell growth and potentiate cisplaitin‐mediated cytotoxicity to colon carcinoma HCT 116 cells

Ras‐ GTP ase‐activating protein SH 3 domain‐binding proteins ( G 3 BP ) are overexpressed in various human tumors and participate in several signaling pathways involved in growth, differentiation and apoptosis. G 3 BP interact with R as GAP ( R as‐ GTP ase activating protein) only in growing cells and depend on R as activation, and participate in the R as signal pathway. Therefore, the blockage and downregulation of G 3 BP may be a new strategy for cancer therapy. In this report, we demonstrate that a novel peptide GAP 161 blocked the functions of G 3 BP and markedly suppressed HCT 116 cell growth through the induction of apoptosis. The peptide bound with G 3 BP , which interfered with the interaction of G 3 BP 1 with R as GAP and further suppressed Ras signaling pathways. GAP 161 downregulated G 3 BP 1 and G 3 BP 2 proteins. Similarly, the knockdown of G 3 BP substantially decreased the proliferation of HCT 116 cells and inhibited R as signal pathways. Furthermore, the downregulation of G 3 BP could enhance cisplatin‐induced apoptosis and growth inhibition of HCT 116 cells. We also found that GAP 161 suppressed the growth of BALB /c mice bearing colon CT 26 tumors and nude mice bearing HCT 116 xenografts. These results suggest that downregulation of G 3 BP might be useful in cancer therapy and that GAP 161 is a promising new therapeutic agent for cancers. ( Cancer Sci , doi: 10.1111/j.1349‐7006.2012.02361.x, 2012)