Ceramides Synthase 6 Participate Apoptosis Of Pancreatic Cancer Induced By Stearoyl-CoA Desaturase-1 Inhibition

Background:pancreatic cancer is a kind of digestive tract tumor with high malignancy.It is famous for its occult onset,rapid progress,early metastasis,strong drug resistance and poor prognosis.Abnormal lipid metabolism is the key factor to promote the development of pancreatic cancer.Therefore,it is of great clinical significance to search for molecular targets to promote apoptosis of pancreatic cancer cells and improve chemotherapeutic drug sensitivity based on lipid metabolism pathway,and to clarify its mechanism.Objective:our previous studies showed that inhibition of SCD1 can promote tumor cell apoptosis by increasing the level of endogenous ceramides.However,the expression of SCD1 and related ceramide in pancreatic cancer has not been reported.Therefore,we will research the communication mechanism of SCD 1/ceramide signaling pathway and its effect on pancreatic cancer cells.Methods:in this study,we collected the tissue samples of patients with pancreatic cancer and their matched paracancerous tissues.And then we detected the expression of SCD1 protein and endogenous ceramide lipid in pancreatic cancer by Western blot,immunohistochemistry,immunofluorescence and HPLC-MS/MS.The human pancreatic cancer cell line PANC-1 was selected to investigate the specific communication mechanism between SCD1 and ceramide by means of siRNA transfection and the use of inhibitors.By combining SCD1 with gemcitabine,the first-line drug of pancreatic cancer,the mechanism of promoting the apoptosis of pancreatic cancer cells and improving the drug resistance of pancreatic cancer after inhibiting SCD1 was revealed.In order to further verify the results of cell experiments,the transplanted tumor model of pancreatic cancer in nude mice was established.Results:the expression of SCD1 in PD AC tissues was higher than that in adjacent tissues.In PANC-1 cells,inhibition of SCD1 can induce apoptosis of pancreatic cancer cells by increasing the content of endogenous ceramide,and enhance the sensitivity of gemcitabine.In pancreatic cancer,inhibition of SCD1 induced overexpression of cers6 selectively catalyzes the biosynthesis of tumor suppressive sphingolipids,such as dihydroceramide.The high expression of cers6 may be due to the over accumulation of SFA level and the activation of p53.Conclusion:the high expression of SCD1 in pancreatic cancer and the inhibition of apoptosis induced by SCD1 are caused by the increase of ceramide expression promoted by the increase of cers6.Targeting SCD1/cers6 combined with gemcitabine may be a new strategy for the treatment of pancreatic cancer.