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Research Article

Small molecule inhibition of GCNT3 disrupts mucin biosynthesis and malignant cellular behaviors in pancreatic cancer

Chinthalapally V. Rao, Naveena B. Janakiram, Venkateshwar Madka, Gaurav Kumar, Scott Edgar, Gopal Pathuri, Taylor Bryant, Hannah Kutsche, Yuting Zhang, Laura Biddick, Hariprasad Gali, Daniel Zhao, Stan Lightfoot and Altaf Mohammed
Chinthalapally V. Rao
Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center
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  • For correspondence: cv-rao@ouhsc.edu
Naveena B. Janakiram
Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center
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Venkateshwar Madka
Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center
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Gaurav Kumar
Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center
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Scott Edgar
Microbiology and Immunology, University of Oklahoma Health Sciences Center
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Gopal Pathuri
Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center
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Taylor Bryant
Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center
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Hannah Kutsche
Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center
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Yuting Zhang
Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center
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Laura Biddick
Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center
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Hariprasad Gali
College of Pharmacy, University of Oklahoma Health Sciences Center
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Daniel Zhao
Biostatistics and Epidemiology, College of Public Health, University of Oklahoma Health Sciences Center
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Stan Lightfoot
Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center
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Altaf Mohammed
Center for Cancer Prevention and Drug Development, Department of Medicine, Hematology/Oncology Section, University of Oklahoma Health Sciences Center
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DOI: 10.1158/0008-5472.CAN-15-2820
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Abstract

Pancreatic cancer (PC) is an aggressive neoplasm with almost uniform lethality and a five-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 PC, next-generation sequencing of genetically engineered Kras-driven mouse pancreatic tumors, and human PC cells to identify the novel core mucin-synthesizing enzyme GCNT3 (core 2 beta 1,6 N-acetylglucosaminyltransferase). In mouse PC tumors, GCNT3 upregulation (103-fold; p<0.0001) was correlated with increased expression of mucins (5-87 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 knock-out of GCNT3 in PC 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.

  • Received October 13, 2015.
  • Revision received December 31, 2015.
  • Accepted January 18, 2016.
  • Copyright © 2016, American Association for Cancer Research.
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Published OnlineFirst February 15, 2016
doi: 10.1158/0008-5472.CAN-15-2820

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Small molecule inhibition of GCNT3 disrupts mucin biosynthesis and malignant cellular behaviors in pancreatic cancer
Chinthalapally V. Rao, Naveena B. Janakiram, Venkateshwar Madka, Gaurav Kumar, Scott Edgar, Gopal Pathuri, Taylor Bryant, Hannah Kutsche, Yuting Zhang, Laura Biddick, Hariprasad Gali, Daniel Zhao, Stan Lightfoot and Altaf Mohammed
Cancer Res February 15 2016 DOI: 10.1158/0008-5472.CAN-15-2820

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Small molecule inhibition of GCNT3 disrupts mucin biosynthesis and malignant cellular behaviors in pancreatic cancer
Chinthalapally V. Rao, Naveena B. Janakiram, Venkateshwar Madka, Gaurav Kumar, Scott Edgar, Gopal Pathuri, Taylor Bryant, Hannah Kutsche, Yuting Zhang, Laura Biddick, Hariprasad Gali, Daniel Zhao, Stan Lightfoot and Altaf Mohammed
Cancer Res February 15 2016 DOI: 10.1158/0008-5472.CAN-15-2820
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