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PP2A Inhibitor PME-1 Drives Kinase Inhibitor Resistance in Glioma Cells.
Kaur, Amanpreet; Denisova, Oxana V; Qiao, Xi; Jumppanen, Mikael; Peuhu, Emilia; Ahmed, Shafiq U; Raheem, Olayinka; Haapasalo, Hannu; Eriksson, John; Chalmers, Anthony J; Laakkonen, Pirjo; Westermarck, Jukka.
Afiliación
  • Kaur A; Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
  • Denisova OV; Department of Pathology, University of Turku, Turku, Finland.
  • Qiao X; TuBS and TuDMM Doctoral Programmes, Turku, Finland.
  • Jumppanen M; Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
  • Peuhu E; Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
  • Ahmed SU; Department of Pathology, University of Turku, Turku, Finland.
  • Raheem O; TuBS and TuDMM Doctoral Programmes, Turku, Finland.
  • Haapasalo H; Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
  • Eriksson J; Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, Finland.
  • Chalmers AJ; Institute of Cancer Sciences, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom.
  • Laakkonen P; Department of Pharmacy, Health and Well-being, Dale Building, Sciences Complex, University of Sunderland, United Kingdom.
  • Westermarck J; Neuromuscular Research Unit, Tampere University and University Hospital, Tampere, Finland.
Cancer Res ; 76(23): 7001-7011, 2016 12 01.
Article en En | MEDLINE | ID: mdl-27671680
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.
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Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores de Proteínas Quinasas / Proteína Fosfatasa 2 / Glioma Límite: Animals / Humans Idioma: En Revista: Cancer Res Año: 2016 Tipo del documento: Article País de afiliación: Finlandia Pais de publicación: Estados Unidos
Buscar en Google
Añadir a Mi BVS
Imprimir
XML
PubMed Links

Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Inhibidores de Proteínas Quinasas / Proteína Fosfatasa 2 / Glioma Límite: Animals / Humans Idioma: En Revista: Cancer Res Año: 2016 Tipo del documento: Article País de afiliación: Finlandia Pais de publicación: Estados Unidos