APE1 Regulates Wnt/?-catenin Signaling Through Its Redox Functional Domain In Pancreatic Cancer Cells

Pancreatic cancer is a life-threatening digestive system neoplasm with a 5-year survival rate of?5%,and the incidence of pancreatic cancer has been increasing worldwide.Apurinic/apyrimidinic endonuclease 1/redox factor-1(APE 1/Ref-1,APE1)is a multifunctional enzyme that is upregulated in human pancreatic cancer.APE1 reduces the level of intracellular ROS by two redox active Cys residues in its N-terminus(Cys65,Cys93).Most researches show that Wnt/p-catenin signaling is associated with cancer promotion and progression.Purpose:We studied whether APE1 affect Wnt/p-catenin signaling,and explored its functions in the pathogenesis of pancreatic cancers.Methods:An APE1 inhibitor E3330 and a Wnt inhibitor IWR-1 were used for cell treating respectively to determined pancreatic cancer cell proliferation and examined the level of ROS and Wnt/?-catenin signaling targeted genes(?-catenin,C-Myc and Cyclin-D1).Treating cells with a combination of APE1 inhibitor and Wnt inhibitor to determined cell proliferation,cell cycle and examined the level of ROS and Wnt/?-catenin signaling correlated genes.Subsequently,the stable APE1 overexpression pancreatic cancer cell lines were established to determined cell proliferation and examined the level of ROS and Wnt/?-catenin signaling targeted genes.Results:Inhibition of APEI resulted in growth suppression of pancreatic cancer cells,increased ROS levels,upregulation of ?-catenin and C-Myc and downregulation of Cyclin D1.Consistent with these data,overexpression of APE1 in pancreatic cancer cells reduced ROS and C-Myc levels and increased Cyclin D1 levels.Treatment of pancreatic cancer cells with the Wnt/?-catenin inhibitor IWR-1 resulted in growth inhibition,which was greatly enhanced when combined with E3330 treatment.Conclusions:APE1 regulates Wnt/?-catenin signaling through its redox functional domain in pancreatic cancer cells,A combination of an APE1 and a Wnt/?-catenin inhibitor had a stronger effect in inhibiting pancreatic cell proliferation,indicating that this inhibitor combination may offer a more promising treatment option in pancreatic cancer therapy.