The tankyrase inhibitor G007-LK inhibits small intestine LGR5+ stem cell proliferation without altering tissue morphology
- Biol Res. 2018 Jan 9;51(1):3. doi: 10.1186/s40659-017-0151-6.
- 1. Department of Cancer Genetics and SFI CAST, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, 0310, Oslo, Norway. [email protected].
- 2. Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, 0310, Oslo, Norway.
- 3. Department of Core Facilities, Oslo University Hospital, The Norwegian Radium Hospital, 0310, Oslo, Norway.
- 4. Department of Biosciences, University of Oslo, 0310, Oslo, Norway.
- 5. Centre for Cancer Biomedicine, 0310, Oslo, Norway.
- 6. Department of Laboratory Medicine, Karolinska Institutet, 141 86, Huddinge, Sweden.
- 7. Unit for Cell Signalling and SFI CAST, Oslo University Hospital, 0310, Oslo, Norway.
- 8. Department of Cancer Genetics and SFI CAST, Institute for Cancer Research, Oslo University Hospital, The Norwegian Radium Hospital, 0310, Oslo, Norway. [email protected].
Background: The Wnt pathway regulates intestinal stem cells and is frequently disrupted in intestinal adenomas. The pathway contains several potential biotargets for interference, including the poly-ADP ribosyltransferase Enzymes tankyrase1 and 2. LGR5 is a known Wnt pathway target gene and marker of intestinal stem cells. The LGR5+ stem cells are located in the crypt base and capable of regenerating all intestinal epithelial cell lineages.
Results: We treated Lgr5-EGFP-Ires-CreERT2;R26R-Confetti mice with the tankyrase inhibitor G007-LK for up to 3 weeks to assess the effect on duodenal stem cell homeostasis and on the integrity of intestinal epithelium. At the administered doses, G007-LK treatment inhibited Wnt signalling in LGR5+ stem cells and reduced the number and distribution of cells traced from duodenal LGR5+ stem cells. However, the gross morphology of the duodenum remained unaltered and G007-LK-treated mice showed no signs of weight loss or any Other visible morphological changes. The inhibitory effect on LGR5+ stem cell proliferation was reversible.
Conclusion: We show that the tankyrase inhibitor G007-LK is well tolerated by the mice, although proliferation of the LGR5+ intestinal stem cells was inhibited. Our observations suggest the presence of a tankyrase inhibitor-resistant cell population in the duodenum, able to rescue tissue integrity in the presence of G007-LK-mediated inhibition of the Wnt signalling dependent LGR5+ intestinal epithelial stem cells.