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

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.

Unlocking the potential ofmiR-19bin the regulation of temozolomide response in glioblastoma patients via targeting PPP2R5E, a subunit of the protein phosphatase 2A complex

“…TMZ-induced H2AX foci formation, CHK1/CHK2 phosphorylation and senescence were significantly enhanced, while TMZ-induced G2/M arrest was reduced in miR-19b attenuated GBM cell lines and GSCs indicating elevated DNA damage. In line with these findings, treating cells with FTY720, which restores PP2A activity by interacting with CIP2A and SET (29) GBM (19). Orthotopic mouse experiments revealed that GSC4 shPPP2R5E tumors were more aggressive and less responsive to TMZ compared to sh(ctrl).…”

“…PP2A inhibiting proteins (PAIP) contribute to PP2A inactivation (19). In our cohort of recurrent GBM, CIP2A and PHAP1 were upregulated in recurrent tumors compared to matched initial tumors (Fig.6A).…”

“…In line with these findings, treating cells with FTY720, which restores PP2A activity by interacting with CIP2A and SET (29), or knocking down CIP2A, PME1 or PHAP1 enhanced TMZ sensitivity mediated by PPP2R5E reactivation. This gene frequently downregulated, but rarely mutated in GBM (19). Orthotopic mouse experiments revealed that GSC4 shPPP2R5E tumors were more aggressive and less responsive to TMZ compared to sh(ctrl).…”

Protein phosphatase 2A modulation and connection with miRNAs and natural products

“…Depending on the context and type of cancer, PP2A may have a dual role for tumor suppressors and promoters by inhibiting oncogenic and anti-oncogenic pathways. 8,9 Therefore, the modulation of PP2A in carcinogenesis is complex and needs thoughtful consideration.…”

“…Protein phosphatases can dephosphorylate phosphate groups of target proteins, reversed by the phosphorylation via protein kinases. Depending on the context and type of cancer, PP2A may have a dual role for tumor suppressors and promoters by inhibiting oncogenic and anti‐oncogenic pathways 8,9 . Therefore, the modulation of PP2A in carcinogenesis is complex and needs thoughtful consideration.…”