After down regulation of integrin beta1, PC9 AB2 cells par tially restored sensitivity to gefitinib while up regulation of integrin beta1 led to resistance of PC9 cells to gefitinib. Expression level of integrin beta1 was nega tively correlated with gefitinib sensitivity in these two cell lines. These information recognized that integrin beta1 is surely an critical issue of EGFR TKIs resistance. Morello also observed that the integrin beta1 silenced cells showed a defective activation of the EGFR signaling cascade, leading to decreased in vitro proliferation, enhanced sensitivity to gefitinib, impaired migration and invasive habits Our final results showed that the two integrin beta1 and c MET had been expressed in these cell lines, and their ligands can improve cell proliferation synergistically. Importantly, inhibition of the two receptors led to development inhibition and apoptosis, and down regulation of phosphorylation of molecules within their downstream signal transduction in the synergistic fashion.
Ligand dependent activation of integrin beta1 induced c MET and its downstream signals activation Mitra et al. also reported that inhibition of B integrin decreased the phosphorylation of c Met, FAK and Src, both in vitro and in vivo. Activation of c Met by its ligand, HGF SF, or overexpression of a consti tutively lively FAK in HeyA8 cells could over e the result of B integrin inhibition on tumor original site cell invasion, indicating that B integrin is upstream of c Met, Src and FAK.
Inhibition of B integrin on cancer cells in two xenograft designs of ovarian cancer metastasis resulted in a major lower of tumor burden, which was independent Linsitinib of the result of B integrin on angiogenesis These data demonstrates that there’s a crosstalk among integrin beta1 and c MET signaling pathways, and it reaches consensus with Beviglias success that the two signaling pathways, integrin ECM and c MET HGF, cooperate synergistically to induce FAK activation in an adhesion dependent manner, major to enhanced cell adhesion and motility In conclusion, we identified the crosstalk between integrin beta1 and c MET through AKT and FAK signaling pathways is extremely crucial in EGFR TKI resistance. Our findings recognized a whole new molecular mechanism of EGFR TKIs resistance, which will present an efficient thera peutic intervention of EGFR TKIs resistance.