CDP-choline accumulation in breast and colorectal cancer cells treated with a GSK-3-targeting inhibitor

摘要

Purpose Glycogen synthase kinase 3 (GSK3) is a key controlling element of many cellular processes including cell-cycle progression and recent studies suggest that GSK3 is a potential anticancer target. Changes in glucose metabolism associated with GSK3 inhibition may impact on lipid synthesis, whilst lipid metabolites can act as molecular response markers. Methods Here, SKBr~3 breast and HCT8 colorectal cancer cells were treated with the GSK3 inhibitor SB216763, and [ ~(14)C (U)] glucose and [~3H] choline incorporation into lipids was determined. Cell extracts from treated cells were subject to ~(31)P NMR spectroscopy. Results SB216763 treatment decreased choline incorporation into lipids and caused an accumulation of CDP-choline which was accompanied by decreased conversion of glucose into lipid components. Conclusion SB216763 profoundly inhibits phospholipid synthesis in cancer cells which demonstrate accumulation of CDPcholine detectable by ~(31)P NMR spectroscopy. Metabolic changes in lipid metabolism present potential response markers to drugs targeting GSK3.