Oncogenic and Metabolic Features of AKT/FOXO signaling in Multiple Myeloma
Multiple Myeloma (MM) is characterized by the clonal expansion of malignant plasma cells in the bone marrow. Despite the improved clinical outcome of MM patients due to novel treatment modalities MM remains practically incurable. MM cells show increased glycolysis and glytaminolysis compared to healthy plasma cells. We examined the role of the PI3K/AKT/FOXO axis on the metabolic state and flexibility of MM cells.
CRISPR Cas9 generated FOXO knockout and control MM cell lines were treated with preclinical AKT inhibitors and subjected to gene expression profiling, metabolic profiling and survival/growth assays
We demonstrate that MM cells largely depend on aerobic glycolysis and have limited glycolytic reserve. We show that AKT kinase activity crucially regulates the expression and activity of genes involved in glycolysis by suppressing FOXO transcription factors. AKT inhibition also resulted in a FOXO-dependent decrease in expression of genes involved in oxidative phosphorylation, resulting in a functional decrease of oxygen consumption. Our preliminary data suggest that AKT and FOXO limit the metabolic flexibility of MM cells with regards to glycolysis and oxidative phosphorylation. Gene expression data from a large MM patient dataset showed that the expression of MM-associated FOXO signature genes define metabolic subgroups that predict overall survival. Finally, by combining AKT inhibitors with inhibitors of glycolytic enzymes in MM cells, we observed a clear potentiating effect, not only on their glycolytic capacity but also on induced cell death.
AKT inhibitors cause a FOXO-dependent decrease in the expression of glycolytic- and TCA cycle enzymes in MM cells. This leads to a decrease in oxidative phosphorylation and glycolytic capacity, thereby sensitizing MM cells for glycolytic inhibitors.