Pan-inhibition of mucins by targeting the enzyme GCNT3

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Mucins such as MUC1, MUC4, MUC5AC, and MUC16 are highly expressed in pancreatic cancer and have diverse consequences including reducing the penetrance of chemotherapeutics. Mucins are secreted or membrane bound highly glycosylated proteins that make up what is recognised as mucus. Cell surface mucins are a major constituent of what is known as the apical glycocalyx of all mucosal epithelia [1]. Most studies have focused on modulating the protein expression of individual mucins, however a new study has identified an enzyme GCNT3 which catalyses the core glycosylation of all mucins [2]. By disrupting GCNT3 one can effectively eliminate the mucus layer generated by pancreatic cancer.

By targeting GCNT3 with CRISPR and the anti-inflammatory drug talniflumate the authors demonstrated reduced viability of pancreatic cancer cell lines. In a genetically engineered mouse model (GEM) the number of precursor lesions to pancreatic cancer were reduced when the mice were treated with talniflumate. This is an interesting strategy to knock out the mucus layer of pancreatic cancer that could increase the permeability of tumours to chemotherapeutics and thus further drug combination studies will be important.

Ref

  1. Linden SK, Sutton P, Karlsson NG, Korolik V, McGuckin MA. Mucins in the mucosal barrier to infection. Mucosal Immunol. 2008 May;1(3):183-97. doi: 10.1038/mi.2008.5. Review. PubMed PMID: 19079178.
  2. Rao, C. V., N. B. Janakiram, V. Madka, G. Kumar, S. Edgar, G. Pathuri, T. Bryant, et al. ‘Small Molecule Inhibition of GCNT3 Disrupts Mucin Biosynthesis and Malignant Cellular Behaviors in Pancreatic Cancer’. Cancer Research, 15 February 2016. doi:10.1158/0008-5472.CAN-15-2820.
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