PP2A Inhibitor PME-1 Drives Kinase Inhibitor Resistance in Glioma Cells

Abstract

Glioblastoma multiforme (GBM) lacks effective therapy options. Although deregulated kinase pathways are drivers of malignant progression in GBM, glioma cells exhibit intrinsic resistance towards many kinase inhibitors, and the molecular basis of this resistance remains poorly understood. Here we show that overexpression of the protein phosphatase 2A (PP2A) inhibitor protein PME-1 drives resistance of glioma cells to various multikinase inhibitors. The PME-1-elicited resistance was dependent on specific PP2A complexes and was mediated by a decrease in cytoplasmic HDAC4 activity.Importantly, both PME-1 and HDAC4 associated with human glioma progression, supporting clinical relevance of the identified mechanism. Synthetic lethality induced by both PME-1 and HDAC4 inhibition was dependent on the co-expression of pro-apoptotic protein BAD. Thus, PME-1-mediated PP2A inhibition is a novel mechanistic explanation for multikinase inhibitor resistance in glioma cells. Clinically, these results may inform patient stratification strategies for future clinical trials with selected kinase inhibitors in GBM. Kaur et al.,3

MKK7 transcription positively or negatively regulated by SP1 and KLF5 depends on HDAC4 activity in glioma

“…Migration or invasion of glioma cells was examined using 24‐well Boyden chambers (Corning Costar Corp., Cambridge, MA) with 8 μM‐inserts coated without or with fibronectin (Sigma‐Aldrich) and Matrigel (BD Biosciences, Bedford, MA) as previously reported . Glioma cells (10 5 cells/well) were plated on the inserts and the lower chamber was filled with 0.5 ml DMEM supplemented with 10% FBS.…”

“…Previous reports have stated that HDAC4 is highly expressed in primary GBMs . Indeed, HDAC4 expression in GBM tissues was far higher than that in the matched peritumoral tissues (Figs.…”

“…HDAC4 nuclear import‐evoked harmful effects have become known as pathological causes for several disease models, such as ataxia telangiectasia, stroke and Parkinson's disease . In glioma cells, HDAC4 activity has been implicated in invasion, proliferation, and drug and radiation resistance . Highly expressed HDAC4 is positively correlated with the tumor grade and negatively correlated with overall survival rates .…”

“…Migration or invasion of glioma cells was examined using 24-well Boyden chambers (Corning Costar Corp., Cambridge, MA) with 8 μM-inserts coated without or with fibronectin (Sigma-Aldrich) and Matrigel (BD Biosciences, Bedford, MA) as previously reported. 16 Glioma cells (10 5 cells/well) were plated on the inserts and the lower chamber was filled with 0.5 ml DMEM supplemented with 10% FBS. After culturing at 37 C for the optimized time course, the cells that crossed the inserts were stained with crystal violet (0.005%, Sigma-Aldrich), and were counted as cells per field of view under phase-contrast microscopy.…”

A SMAP in the face for cancer

“…In this regard, PP2A heterotrimers containing the B55α subunit, which is predominantly expressed in brain, appear to be particularly reliant on C subunit methylation. As increased PME-1 activity has been implicated in the resistance of gliomas to a variety of kinase inhibitors (13), one could speculate that PME-1 inhibitors might be particularly useful in the treatment of gliomas and other brain disorders, such as Alzheimer's and Parkinson's disease, that have been linked to reduced PP2A function.…”