The Role And Mechanism Of G Alpha I In The Activation Of PI3K-Akt-mTOR Signaling Pathway Induced By Hepatocyte Growth Factor

ObjectivePancreatic cancer has remained one of the most common malignant tumor with an extremely low 5-year survival rate.The lack of effective anti-pancreatic cancer drugs is one of the important reasons leading to poor prognosis.In recent years,reserch in targeting the molecular and cellular signaling pathways has become important direction for treating pancreatic cancer.Binding of HGF/SF to MET activates various signalling pathways including PI3K-Akt-mTOR and ERK-MAPK,which induce survival,as well as mitogenic and motogenic responses.However,it still remains unclear that the specific mechanism of inducing PI3K-Akt-mTOR and ERK-MAPK signaling pathway by HGF/c-MET.Here is a study to investigate the effects of HGF/c-MET on the biological behavior of pancreatic cancer cells and to analyze the mechanism of inducing downstream signaling pathways.Methods1)MTT assay and clonogenicity assay were applied to test the potential role of HGF on pancreatic cancer cells survival and proliferation.2)After Gαi-shRNA lentivirus interfered the expression of Gαi,we observed the effect of Gαi on survival and proliferation in pancreatic cancer cells.3)To investigate the role and mechanism of Gαi1/3 in the activation of PI3K-Akt-mTOR signaling pathway induced by HGF,Western Blot was applied to test expression of associated protein of PI3K-Akt-mTOR and ERK-MAPK signaling pathway and Gαi in MEFs and pancreatic cancer cells.Results1)HGF stimulates the survival and proliferation of pancreatic cancer cells in vitro.2)Interfering the expression of Gαi by Gαi-shRNA lentivirus inhibit significantly the survival and proliferation of pancreatic cancer cells.3)Gαi1 and Gαi3 are required for HGF-Mediated activation PI3K-Akt-mTOR and ERK-MAPK pathway in MEFs and pancreatic cancer cells.4)Gαi,lying upstream of Gab1,is required for HGF-induced activation of PI3K-Akt-mTOR and ERK-MAPK pathway.Conclusionc-MET activates its downstream PI3K-Akt-mTOR,ERK-MAPK signaling pathway by binding with HGF,and promotes proliferation and clone formation of pancreatic cancer cell.Gαi is a key protein in this signaling pathway and plays an important role in promoting cell survival of pancreatic cancer.