Protein Phosphatases—A Touchy Enemy in the Battle Against Glioblastomas: A Review

Abstract

Glioblastoma (GBM) is the most common malignant tumor arising from brain parenchyma. Although many efforts have been made to develop therapies for GBM, the prognosis still remains poor, mainly because of the difficulty in total resection of the tumor mass from brain tissue and the resistance of the residual tumor against standard chemoradiotherapy. Therefore, novel adjuvant therapies are urgently needed. Recent genome-wide analyses of GBM cases have clarified molecular signaling mechanisms underlying GBM biology. However, results of clinical trials targeting phosphorylation-mediated signaling have been unsatisfactory to date. Protein phosphatases are enzymes that antagonize phosphorylation signaling by dephosphorylating phosphorylated signaling molecules. Recently, the critical roles of phosphatases in the regulation of oncogenic signaling in malignant tumor cells have been reported, and tumorigenic roles of deregulated phosphatases have been demonstrated in GBM. However, a detailed mechanism underlying phosphatase-mediated signaling transduction in the regulation of GBM has not been elucidated, and such information is necessary to apply phosphatases as a therapeutic target for GBM. This review highlights and summarizes the phosphatases that have crucial roles in the regulation of oncogenic signaling in GBM cells.

Function of Glia in Aging and the Brain Diseases

“…Astrocytes are strongly associated with cancer in the brain 56 as cancerous astrocytoma. There are three different astrocytoma types, pilocytic, diffuse and anaplastic astrocytoma.…”

Monotherapy efficacy of blood–brain barrier permeable small molecule reactivators of protein phosphatase 2A in glioblastoma

“…Another potential reason is non-mutational plasticity induced by kinase inhibitors in GB cells ( van den Heuvel et al , 2017 ). Notably, phosphorylation of GB driver pathways is not only regulated by kinases, but also by phosphatases ( Narla et al , 2018 ; Tomiyama et al , 2019 ). Amongst them, protein phosphatase 2A (PP2A) is a serine/threonine phosphatase that regulates multiple oncogenic kinase signalling pathways, as well as apoptotic mechanisms ( Perrotti and Neviani, 2013 ; Kauko and Westermarck, 2018 ).…”

“…Inhibition of these PP2A inhibitor proteins restricts GB cell growth, and PME-1-mediated PP2A inhibition drives widespread kinase inhibitor resistance in GB ( Kaur et al , 2016 ). Because PP2A is non-genetically inactivated in GB by the PAIPs, it could be a suitable target for tumour suppressor reactivation therapies ( Westermarck, 2018 ; Tomiyama et al , 2019 ).…”

Enhanced Malignant Phenotypes of Glioblastoma Cells Surviving NPe6-Mediated Photodynamic Therapy are Regulated via ERK1/2 Activation

“…Under severe cellular stresses, both phosphorylation-mediated signal transduction and dephosphorylation-mediated negative feedback are triggered in RTK signaling [38][39][40][41][42][43]. In particular, in ERK1/2-dependent signaling, dephosphorylation of ERK1/2-and ERK1/2-dependent signaling molecules by protein phosphatases, such as protein phosphatase 2A (PP2A) or dual-specificity phosphatases (DUSPs), has previously been demonstrated [41][42][43]. Therefore, we investigated the expression of PP2A subunit C and DUSP6 by immunoblotting; however, the expression levels of both phosphatases in NPe6-DT-R cells were not altered during 14 days after NPe6-PDT (data not shown).…”