Mucin impedes cytotoxic effect of 5-FU against growth of human pancreatic cancer cells: overcoming cellular barriers for therapeutic gain.
Mucins are high molecular weight glycoproteins expressed on the apical surface of normal epithelial cells. In cancer disease mucins are overexpressed on the entire cellular surface. Overexpression of MUC1 mucin in pancreatic tumours has been correlated with poor patient survival. Current chemotherapeutic approaches such as 5-fluorouracil (5-FU) has produced limited clinical success. In this study we investigated the role of mucin in cytotoxic drug treatment to determine whether the extracellular domain of mucin impedes cytotoxic drug action of 5-FU. Human pancreatic cancer cells revealed high and relatively moderate MUC1 levels for Capan-1 and HPAF-II, respectively, compared to MUC1 negative control (U-87 MG glioblastoma) that showed relatively non-specific anti-MUC1 uptake. Benzyl-alpha-GalNAc (O-glycosylation inhibitor) was used to reduce mucin on cell surfaces, and neuraminidase was used to hydrolyse sialic acid at the distal end of carbohydrate chains. Benzyl-alpha-GalNAc had no effect on cell morphology or proliferation at the concentrations employed. The inhibition of O-glycosylation resulted in significant 5-FU antiproliferative activity against Capan-1 and HPAF-II, but not against U-87 MG. However, the exposure of cells to neuraminidase failed to improve the cytotoxic action of 5-FU. Our experimental findings suggest that the overexpression of mucin produced by human pancreatic tumours might limit the effectiveness of chemotherapy.
Kalra
A V
AV
Department of Pharmaceutical Sciences, Northeastern University, 360 Huntington Avenue, Bouvé College of Health Sciences, Boston, MA 02115, USA.
Campbell
R B
RB
D000116:Acetylgalactosamine / Q000031:analogs & derivatives / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D001593:Benzyl Compounds / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D005472:Fluorouracil / Q000494:pharmacology*; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D006031:Glycosylation; D006801:Humans; D008856:Microscopy, Fluorescence; D018396:Mucin-1 / Q000378:metabolism*; D019158:N-Acetylneuraminic Acid / Q000378:metabolism; D009439:Neuraminidase / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000964:Antimetabolites, Antineoplastic; D001593:Benzyl Compounds; D018396:Mucin-1; C080739:benzyl-alpha-N-acetylgalactosamine; D009439:Neuraminidase; D019158:N-Acetylneuraminic Acid; D000116:Acetylgalactosamine; D005472:Fluorouracil