title: Small-Molecule Inhibition of GCNT3 Disrupts Mucin Biosynthesis and Malignant Cellular Behaviors in Pancreatic Cancer.
abstract: Pancreatic cancer is an aggressive neoplasm with almost uniform lethality and a 5-year survival rate of 7%. Several overexpressed mucins that impede drug delivery to pancreatic tumors have been therapeutically targeted, but enzymes involved in mucin biosynthesis have yet to be preclinically evaluated as potential targets. We used survival data from human patients with pancreatic cancer, next-generation sequencing of genetically engineered Kras-driven mouse pancreatic tumors and human pancreatic cancer cells to identify the novel core mucin-synthesizing enzyme GCNT3 (core 2 β-1,6 N-acetylglucosaminyltransferase). In mouse pancreatic cancer tumors, GCNT3 upregulation (103-fold; P < 0.0001) was correlated with increased expression of mucins (5 to 87-fold; P < 0.04-0.0003). Aberrant GCNT3 expression was also associated with increased mucin production, aggressive tumorigenesis, and reduced patient survival, and CRISPR-mediated knockout of GCNT3 in pancreatic cancer cells reduced proliferation and spheroid formation. Using in silico small molecular docking simulation approaches, we identified talniflumate as a novel inhibitor that selectively binds to GCNT3. In particular, docking predictions suggested that three notable hydrogen bonds between talniflumate and GCNT3 contribute to a docking affinity of -8.3 kcal/mol. Furthermore, talniflumate alone and in combination with low-dose gefitinib reduced GCNT3 expression, leading to the disrupted production of mucins in vivo and in vitro Collectively, our findings suggest that targeting mucin biosynthesis through GCNT3 may improve drug responsiveness, warranting further development and investigation in preclinical models of pancreatic tumorigenesis. Cancer Res; 76(7); 1965-74. ©2016 AACR.
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. cv-rao@ouhsc.edu altaf-mohammed@ouhsc.edu.
authors.forename: Chinthalapally V
authors.initials: CV
authors.lastname: Rao
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Naveena B
authors.initials: NB
authors.lastname: Janakiram
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Venkateshwar
authors.initials: V
authors.lastname: Madka
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Gaurav
authors.initials: G
authors.lastname: Kumar
authors.affiliation: Department of Microbiology and Immunology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Edgar J
authors.initials: EJ
authors.lastname: Scott
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Gopal
authors.initials: G
authors.lastname: Pathuri
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Taylor
authors.initials: T
authors.lastname: Bryant
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Hannah
authors.initials: H
authors.lastname: Kutche
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Yuting
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Laura
authors.initials: L
authors.lastname: Biddick
authors.affiliation: College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Hariprasad
authors.initials: H
authors.lastname: Gali
authors.affiliation: Biostatistics and Epidemiology, College of Public Health, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Yan D
authors.initials: YD
authors.lastname: Zhao
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Stan
authors.initials: S
authors.lastname: Lightfoot
authors.affiliation: Center for Cancer Prevention and Drug Development, Department of Medicine, Hem-Onc Section, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. cv-rao@ouhsc.edu altaf-mohammed@ouhsc.edu.
authors.forename: Altaf
authors.initials: A
authors.lastname: Mohammed
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D018396:Mucin-1 / Q000378:metabolism*; D017351:N-Acetylglucosaminyltransferases / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis; D046888:Tissue Array Analysis; D014162:Transfection
chemical_list: D018396:Mucin-1; D017351:N-Acetylglucosaminyltransferases; C117361:beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-N-acetylglucosaminyltransferase 3