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

A Kaur, OV Denisova, X Qiao, M Jumppanen, E Peuhu, SU Ahmed, O Raheem, H Haapasalo, John Eriksson, AJ Chalmers, P Laakkonen, J Westermarck

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24 Citations (Scopus)

Abstract

Glioblastoma multiforme lacks effective therapy options. Although deregulated kinase pathways are drivers of malignant progression in glioblastoma multiforme, glioma cells exhibit intrinsic resistance toward 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 coexpression of proapoptotic 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 glioblastoma multiforme.
Original languageUndefined/Unknown
Pages (from-to)7001–7011
Number of pages11
JournalCancer Research
Volume76
Issue number23
DOIs
Publication statusPublished - 2016
MoE publication typeA1 Journal article-refereed

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