Enhanced Glycolysis Induced By MUC1 Promotes Drug-resistance In Pancreatic Cancer

Objective: MUC1 is a master regulator of glycolysis in pancreatic cancer.Mannose was reported to be able to block glycolysis of pancreatic cancer cells.The study is aimed to explore the mechanism of metabolism regulation by MUC1 and how MUC1 enhances resistance to mannose in pancreatic cancer.Methods: Western blot was performed to detect expression of MPI in multiple pancreatic cancer cell lines.Growth curve was measured to assess the effect of mannose on proliferation of pancreatic cacer cells.Mass spectrum was used to measure the metabolites in glycolysis after cells were treated with mannose.Chromatin immunoprecipitation was performed to confirm the binding of HIF-1? with promoter of MPI gene.MUC1 and HIF-1? were knocked out using Crispr/Cas9 technology in CFPAC-1 and Capan-1 cell lines.MPI level,growth curve and metabolites levels were measured in knockout cells.We implanted Pa Tu 8902 cells orthotopically in nude mice and mannose plus FOLFIRINOX were used to treat the mice.Morever,BRCA1 level was also dected in MUC1 knockout cells.Glucose uptake assay and lactate release assay were performed after cells were treated with BRCA1 inhibitor.Wild type and MUC1 knockout cells were implanted into nude mice.We treated the mice with FOLFIRINOX and measured the volume of the tumors.Results: Capan-1 and CFPAC-1 cells express high level of MPI,while HPAF2 and Pa Tu 8902 express low level of MPI.Mannose inhibited proliferation of pancreatic cacner cells with low expression of MPI.Mass spectrum showed that metabolites in glycolysis were significantly decreased after mannose treatment.HIF-1? could bind to promoter of MPI gene regulating expression of MPI.MUC1 enhanced HIF-1? protein level.Knock out MUC1 or HIF-1 ? sensitized cells to mannose.Combination therapy using mannose plus FOLFIRINOX achieved better effect than FOLFIRINOX alone in vivo.BRCA1 expression increased significantly in MUC1 knockout cells.Glucose uptake and lactate release increased significantly after BRCA1 inhibitor treatment.MUC1 knockout cells were more sensitive to FOLFIRINOX in vivo.Conclusions: MUC1 promotes glycolysis in pancreatic cancer.MUC1 enhances protein level of HIF-1? and further promotes expression of MPI.High expression of MPI enables cells to gain resistance to mannose.MUC1 can also promote glycolysis by inhibiting BRCA1 expression in pancreatic cancer.