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PP2A inhibitor PME-1 drives kinase inhibitor resistance in glioma cells

Kaur, A., Denisova, O., Qiao, X., Jumppanen, M., Peuhu, E., Ahmed, Shafiq, Raheem, O., Haapasalo, H. K., Eriksson, J., Chalmers, A. J., Laakkonen, P. M. and Westermarck, J. (2016) PP2A inhibitor PME-1 drives kinase inhibitor resistance in glioma cells. Cancer Research, 76 (23). pp. 7001-7011. ISSN 0008-5472

Item Type: Article

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.

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More Information

Depositing User: Barry Hall

Identifiers

Item ID: 6784
Identification Number: https://doi.org/10.1158/0008-5472.CAN-16-1134
ISSN: 0008-5472
URI: http://sure.sunderland.ac.uk/id/eprint/6784
Official URL: http://cancerres.aacrjournals.org/content/early/20...

Users with ORCIDS

ORCID for Shafiq Ahmed: ORCID iD orcid.org/0000-0001-8701-6889

Catalogue record

Date Deposited: 02 Nov 2016 16:27
Last Modified: 30 Sep 2020 11:15

Contributors

Author: Shafiq Ahmed ORCID iD
Author: A. Kaur
Author: O. Denisova
Author: X. Qiao
Author: M. Jumppanen
Author: E. Peuhu
Author: O. Raheem
Author: H. K. Haapasalo
Author: J. Eriksson
Author: A. J. Chalmers
Author: P. M. Laakkonen
Author: J. Westermarck

University Divisions

Faculty of Health Sciences and Wellbeing
Faculty of Health Sciences and Wellbeing > School of Pharmacy and Pharmaceutical Sciences

Subjects

Sciences > Pharmacy and Pharmacology

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