Synergistic anticancer effect of Grb2 and ITGA1 on cancer cells highly expressing Grb2 through suppressing ERK phosphorylation

Background: Growth factor receptor bound protein 2 (Grb2) is known to be an adaptor protein that provides a critical link between cell surface growth factor receptors and the MAPK signaling. It was shown that high expression of Grb2 enhances cancer cells proliferation, invasion and malignant transformation. Objective: In this study, we aimed to systemically understand the function of Grb2 in cancer. Methods: The expression of Grb2 in different cancer cell lines was examined from a publicly available database and we chose two cancer cell lines highly expressing Grb2 to investigate the role of Grb2. To systemically understand the function of Grb2 in cancer cells, proteomic profiles also were analyzed. Result: The results suggested that downregulation of Grb2 reduced cell proliferation in Hela cells and Jurkat cells. In addition, knockdown of Grb2 reduced the expression of ITGA1 and inhibited the phosphorylation of ERK. Intriguingly, simultaneous inhibition of Grb2 and ITGA1 resulted in a greater inhibition of phosphorylated ERK than either inhibition of Grb2 or ITGA1, and thus triggered marked apoptosis in Hela cells and Jurkat cells. These results suggest a synergistic anticancer effect of Grb2 and ITGA1 mediated by the ERK pathway in cancer cells highly expressing Grb2. In conclusion, we provided evidence that inhibition of Grb2 and ITGA1 might be an attractive target for therapeutic intervention against the cancer growth of cancers with high Grb2 expression.