TIGAR Is Required for Efficient Intestinal Regeneration and Tumorigenesis

Regulation of metabolic pathways plays an important role in controlling cell growth, proliferation, and survival. TIGAR acts as a fructose-2,6-bisphosphatase, potentially promoting the pentose phosphate pathway to produce NADPH for antioxidant function and ribose-5-phosphate for nucleotide synthesis. The functions of TIGAR were dispensable for normal growth and development in mice but played a key role in allowing intestinal regeneration in vivo and in ex vivo cultures, where growth defects due to lack of TIGAR were rescued by ROS scavengers and nucleosides. In a mouse intestinal adenoma model, TIGAR deficiency decreased tumor burden and increased survival, while elevated expression of TIGAR in human colon tumors suggested that deregulated TIGAR supports cancer progression. Our study demonstrates the importance of TIGAR in regulating metabolism for regeneration and cancer development and identifies TIGAR as a potential therapeutic target in diseases such as ulcerative colitis and intestinal cancer. [Display omitted] •TIGAR is expressed in most adult tissue but is dispensable for embryonic development•Intestinal damage induces TIGAR, which is important for gut regeneration•TIGAR provides reducing power and nucleotides for rapid intestinal proliferation•TIGAR contributes to the development of intestinal tumors in mice and humans TIGAR enhances NADPH and nucleotide precursor generation for antioxidant and DNA production. Cheung et al. show that TIGAR is important for intestinal tissue regeneration despite being dispensable for development. TIGAR deficiency also impeded intestinal tumor development. As human colon cancers overexpress TIGAR, its inhibition may selectively target tumor growth.