Pleiotropy of PP2A Phosphatases in Cancer with a Focus on Glioblastoma IDH Wildtype

SIMPLE SUMMARY: GBM is a highly heterogeneous tumor owing to incredible cellular plasticity and adaptation to hypoxia, nutrient availability and therapy. This plasticity is in part due to the dynamic switch of oncogenic pathways that drive GBM progression, generating subclones with distinct alterations in pro-survival signaling pathways. Consequently, despite addiction to specific oncogenic mutations in some GBM subclones, targeted therapies with small molecule kinase inhibitors have very limited efficacy due to the rapid outgrowth of other subclones with a different set of driver mutations. PP2A can simultaneously target many integral inducers of these driver pathways including EGFR, NF-κB, and Wnt kinases. Therefore, PP2A modulation has potential as an adjuvant therapy, as it can drive plastic GBM cells into a dead-end in which they no longer can bear the effects of treatment due to lack of alternative escape pathways. ABSTRACT: Serine/Threonine protein phosphatase 2A (PP2A) is a heterotrimeric (or occasionally, heterodimeric) phosphatase with pleiotropic functions and ubiquitous expression. Despite the fact that they all contribute to protein dephosphorylation, multiple PP2A complexes exist which differ considerably by their subcellular localization and their substrate specificity, suggesting diverse PP2A functions. PP2A complex formation is tightly regulated by means of gene expression regulation by transcription factors, microRNAs, and post-translational modifications. Furthermore, a constant competition between PP2A regulatory subunits is taking place dynamically and depending on the spatiotemporal circumstance; many of the integral subunits can outcompete the rest, subjecting them to proteolysis. PP2A modulation is especially important in the context of brain tumors due to its ability to modulate distinct glioma-promoting signal transduction pathways, such as PI3K/Akt, Wnt, Ras, NF-κb, etc. Furthermore, PP2A is also implicated in DNA repair and survival pathways that are activated upon treatment of glioma cells with chemo-radiation. Depending on the cancer cell type, preclinical studies have shown some promise in utilising PP2A activator or PP2A inhibitors to overcome therapy resistance. This review has a special focus on “glioblastoma, IDH wild-type” (GBM) tumors, for which the therapy options have limited efficacy, and tumor relapse is inevitable.