PP2A Inhibitor PME-1 Drives Kinase Inhibitor Resistance in Glioma Cells.
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.
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.|Department of Pathology, University of Turku, Turku, Finland.|TuBS and TuDMM Doctoral Programmes, Turku, Finland.
Amanpreet
A
Kaur
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
Oxana V
OV
Denisova
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.|Department of Pathology, University of Turku, Turku, Finland.|TuBS and TuDMM Doctoral Programmes, Turku, Finland.
Xi
X
Qiao
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
Mikael
M
Jumppanen
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
Emilia
E
Peuhu
Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom.|Department of Pharmacy, Health and Well-being, Dale Building, Sciences Complex, University of Sunderland, United Kingdom.
Shafiq U
SU
Ahmed
Neuromuscular Research Unit, Tampere University and University Hospital, Tampere, Finland.|Division of Pathology and Genetics, HUSLAB, Helsinki, Finland.
Olayinka
O
Raheem
Department of Pathology, Fimlab Laboratories, Tampere, Finland.
Hannu
H
Haapasalo
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.|Department of Biosciences, Åbo Akademi University, Turku, Finland.
John
J
Eriksson
Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom.
Anthony J
AJ
Chalmers
Research Programs Unit, Translational Cancer Research and Laboratory Animal Centre, University of Helsinki, Helsinki, Finland.
Pirjo
P
Laakkonen
Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland. jukwes@utu.fi.|Department of Pathology, University of Turku, Turku, Finland.
Jukka
J
Westermarck
D000818:Animals; D005910:Glioma / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D014162:Transfection
D047428:Protein Kinase Inhibitors; D054648:Protein Phosphatase 2