KO of 5-InsP ₇ kinase activity transforms the HCT116 colon cancer cell line into a hypermetabolic, growth-inhibited phenotype

Significance Therapeutic improvements to human health can accrue from understanding the bidirectional relationship between cell signaling and bioenergetic homeostasis. Key players in this communication interface are inositol pyrophosphate cellular signals 5-InsP 7 and 1,5-InsP 8 , which are interconverted by diphosphoinositol pentakisphosphate kinases (PPIP5Ks). Here, an intestinal tumor cell line is used for CRISPR-based KO of PPIP5Ks, which eliminates 1,5-InsP 8 and raises 5-InsP 7 levels several fold. PPIP5K −/− cells exhibit a growth-inhibited phenotype, indicating that PPIP5Ks are potential targets for tumor therapy. PPIP5K −/− cells also have elevated levels of ATP because of increased mitochondrial biomass and accelerated rates of glycolysis. This hypermetabolic state is attributed to hitherto unsuspected functions for 1,5-InsP 8 in bioenergetic homeostasis, thereby suggesting that PPIP5Ks could offer approaches to treat metabolic diseases.