PP2A Inhibitor PME-1 Drives Kinase Inhibitor Resistance in Glioma Cells
Authors: Anthony J Chalmers
Xi Qiao
Pirjo Laakkonen
Mikael Jumppanen
Shafiq U Ahmed
Amanpreet Kaur
Emilia Peuhu
Olayinka Raheem
Oxana V Denisova
Hannu Haapasalo
Jukka Westermarck
John Eriksson
Journal: Cancer Research (2016)
Discipline: CLINICAL MEDICINE
Keywords: Glioblastoma multiforme; kinase inhibitors; protein phosphatase 2A (PP2A); PME-1; resistance
Affiliations: Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland., Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom., Neuromuscular Research Unit, Tampere University and University Hospital, Tampere, Finland., Department of Pathology, Fimlab Laboratories, Tampere, Finland., Research Programs Unit, Translational Cancer Research and Laboratory Animal Centre, University of Helsinki, Helsinki, Finland., Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland. .

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. Cancer Res; 76(23); 7001-11. ©2016 AACR. 

Retracted: No

PubPeer comments:
 There appears to be a figure assembly error in Figure 2. The images in Figure 2B and 2C seem to be the same. Could the authors please check? *** ![file] , 
 Thank you for notifying us abut this very unfortunate and unintentional error. However, this does not by any means compromise the reliability of the conclusions from these experiments as quantifications including statistical analysis is presented next to data from both cell lines and they both show very significant impact of PME-1 inhibition on GB cell response to STS derivative s. Importantly though the quantifications are not identical between the cell lines, proving that they are based on data from different cell lines behaving slightly differently. Very recently we submitted a follow-up paper where we extended the importance of PME-1 mediated PP2A inhibition on multikinase inhibitor resistance to even larger number of brain cancer cell lines and glioma stem cells demonstrating that the results are fully repeatable across cell lines . Again, we apologise for the mistake but are confident that there are no need for any further actions related to potential reliability of the data. , 
 #2 Thank you for your response. It is very clear that this is just a figure assembly error, but leaving the figure as-is may cause confusion and doubt in future readers. If I would view these figures, I would draw the quality of the paper into question. Would it perhaps be a possibility for the authors to contact the editor and propose an erratum? Many papers nowadays have small editorial mistakes - correcting these is both trivial and the right thing to do to uphold the academic record. ,