AKT signaling restrains tumor suppressive functions of FOXO transcription factors and GSK3 kinase in multiple myeloma

Abstract

The phosphatidylinositide-3 kinases and the downstream mediator AKT drive survival and proliferation of multiple myeloma (MM) cells. AKT signaling is active in MM and has pleiotropic effects; however, the key molecular aspects of AKT dependency in MM are not fully clear. Among the various downstream AKT targets are the Forkhead box O (FOXO) transcription factors (TFs) and glycogen synthase kinase 3 (GSK3), which are negatively regulated by AKT signaling. Here we show that abrogation of AKT signaling in MM cells provokes cell death and cell cycle arrest, which crucially depends on both FOXO TFs and GSK3. Based on gene expression profiling, we defined a FOXO-repressed gene set that has prognostic significance in a large cohort of patients with MM, indicating that AKT-mediated gene activation is associated with inferior overall survival. We further show that AKT signaling stabilizes the antiapoptotic myeloid cell leukemia 1 (MCL1) protein by inhibiting FOXO- and GSK3-mediated MCL1 turnover. In concordance, abrogation of AKT signaling greatly sensitized MM cells for an MCL1-targeting BH3-mimetic, which is currently in clinical development. Taken together, our results indicate that AKT activity is required to restrain the tumor-suppressive functions of FOXO and GSK3, thereby stabilizing the antiapoptotic protein MCL1 in MM. These novel insights into the role of AKT in MM pathogenesis and MCL1 regulation provide opportunities to improve targeted therapy for patients with MM.

Metabolic Effects of Recurrent Genetic Aberrations in Multiple Myeloma

“…Importantly, we have recently demonstrated that activation of FOXO induces cell cycle arrest and cell death of MM cells. In agreement, inhibition of AKT in MM cells decreased MYC expression and activity [ 65 ]. MYC-driven lymphomas in experimental mouse models almost uniformly lose ARF or p53 expression [ 61 ], and in human Burkitt lymphoma TP53 is lost in a large fraction of the cases [ 66 ].…”

“…DHODH is expressed in MM cells and is essential for cell growth, as it was demonstrated that the specific DHODH inhibitor A771726 induced a G1 cell cycle arrest in MM cell lines. Interestingly, A771726 also inhibited AKT signaling [ 141 ], which could potentially interfere with MYC expression and activity in MM cells by activating FOXO [ 65 ]. In agreement, DHODH inhibitors and DHODH knockdown downregulated MYC expression in MM cells [ 142 ].…”

FOXO1 mitigates the SMAD3/FOXL2C134W transcriptomic effect in a model of human adult granulosa cell tumor

“…It is well known that AKT inhibits FOXO through direct phosphorylation [ 86 , 87 ]. Notably, FOXO1 can be indirectly targeted via the action of AKT inhibitors [ 88 – 91 ].…”

Pathobiology and Therapeutic Relevance of GSK-3 in Chronic Hematological Malignancies

“…There is a study which demonstrates how GSK-3 potentially has tumor-suppressive functions in MM; however, its activity is restrained by Akt activation, thereby resulting in the stabilization of Mcl-1 levels [ 157 ]. Another restrainer of GSK-3 in MM cells is the histone demethylase KDM4C, which is upregulated in MM patients and, when overexpressed in MM cell lines, increases β-catenin levels and activity while decreasing both the RNA and protein expression of GSK-3β [ 158 ].…”