Molecular events that determine the functional outcome of GSK3 inhibition

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Recent years have brought a growing appreciation of the intricate links between cell signaling and metabolism. While extracellular activation results in metabolic reprograming to meet the biosynthetic and energetic needs of proliferating cells, changes in the extracellular metabolic microenvironment, the activity of metabolic enzymes or the pools of intracellular metabolites can profoundly affect cell signaling and thus cell fate and function. In our previous work we have identified the glycogen synthase kinase 3 (GSK3)/ β-catenin signaling axis to play a crucial role in coordinating B cell fate decisions with metabolic activity. We could show that GSK3 inhibition/ β-catenin accumulation enhances mitochondrial activity resulting in increased cell mass and proliferation. On the other hand, we found GSK3 inhibition/β-catenin accumulation to result in increased production of reactive oxygen species and higher susceptibility to different types of stress such as DNA damage or nutrient restriction. Interestingly, we found B cell precursors to be more sensitive to β-catenin accumulation than mature B cells. Taken together these findings argue for a context-dependent role of the GSK3/ β-catenin signaling pathway. Our aim now is to identify the signaling events that tip the balance between increased metabolic activity and cell death in GSK3-inhibited B cells, to further clarify the role of GSK3/ β-catenin in genotoxic stress responses and to provide insight into the role of β-catenin in mitochondrial metabolism. GSK3 inhibitors are safe to use in humans. A better understanding of the role of the GSK3/ β-catenin signaling network is needed in order to explore potential therapeutic use of GSK3 inhibitors in B cell malignancies.