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Tumor Biology 25: Molecular and Cellular Aspects of Tumor Invasion

Abstract #3513

A specific peptide ligand for Grb7 adaptor protein inhibits invasion and metastasis of pancreatic cancer

Tokyo Medical and Dental University, Tokyo, Japan, University of Vermont School of Medicine, Burlington, VT, National Kyushu Cancer Center, Fukuoka, Japan, University of Tokushima, Tokushima, Japan, Kyushu University, Beppu, Japan

Pancreatic cancer, among the most aggressive of all human malignancies, remains an unfortunate disease. Invasive and metastatic spread of tumor cells is the major risk factor affecting clinical prognosis of patients with pancreatic cancer. One of the key mechanisms required for invasion and metastasis of tumor cells involves the transmission of intracellular signals following activation of protein tyrosine kinases. Subsequent tyrosyl phosphorylation of intracellular substrates leads to an interaction with SH2 domains of downstream signaling molecules. Based on analysis of clinical samples, we isolated an SH2-containing adaptor protein Grb7 as a molecule frequently overexpressed in invasive and metastatic human cancer. It should be mentioned that the predicted protein of Grb7 shares structural homology with a cell migration molecule designated Mig-10 found in Caenorhabditis elegans. In vitro, knock down of Grb7 gene strikingly diminished cell migration of the cultured pancreas cancer cells. Although the phosphotyrosine-containing peptides with a minimal recognition motif are sufficient to compete with in vitro protein ligands for SH2 domain binding, a major difficulty in designing such inhibitors is the phosphatase lability that renders phosphotyrosine-containing inhibitors unsuitable for in vivo studies. Using phage-display technology, we identified a non-phosphorylated cyclic peptide with selective affinity to SH2 domain of Grb7. In pancreatic cancer cells, the Grb7 peptide inhibitor blocked the association of Grb7 with protein tyrosine kinases as well as tyrosyl phosphorylation of the Grb7 protein, but not the interaction of other endogenous SH2-containing proteins with protein tyrosine kinases. Additionally, the Grb7 peptide inhibitor completely attenuated in vivo cell invasion, as well as peritoneal metastasis of the pancreatic cancer cells in animal models. Our results suggest the Grb7 peptide inhibitor might be a promising agent for molecular targeted therapeutics against pancreatic cancer.