Targeting class IA PI3K isoforms selectively impairs cell growth, survival, and migration in glioblastoma

Katrin Höland; Danielle Boller; Christian Hagel; Silvia Dolski; András Treszl; Olivier E Pardo; Paulina Cwiek; Fabiana Salm; Zaira Leni; Peter R Shepherd; Beata Styp-Rekowska; Valentin Djonov; André O von Bueren; Karl Frei; Alexandre Arcaro

doi:10.1371/journal.pone.0094132

Targeting class IA PI3K isoforms selectively impairs cell growth, survival, and migration in glioblastoma

PLoS One. 2014 Apr 9;9(4):e94132. doi: 10.1371/journal.pone.0094132. eCollection 2014.

Authors

Affiliations

¹ Department of Clinical Research, University of Bern, Bern, Switzerland.
² Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland.
³ Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁴ Department of Neurosurgery, University Hospital Zurich, Zurich, Switzerland.
⁵ Department of Medical Biometry and Epidemiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
⁶ Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
⁷ Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand.
⁸ Institute of Anatomy, University of Bern, Bern, Switzerland.
⁹ Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center Goettingen, Goettingen, Germany.
¹⁰ Department of Clinical Research, University of Bern, Bern, Switzerland; Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland.

Abstract

The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway is frequently activated in human cancer and plays a crucial role in glioblastoma biology. We were interested in gaining further insight into the potential of targeting PI3K isoforms as a novel anti-tumor approach in glioblastoma. Consistent expression of the PI3K catalytic isoform PI3K p110α was detected in a panel of glioblastoma patient samples. In contrast, PI3K p110β expression was only rarely detected in glioblastoma patient samples. The expression of a module comprising the epidermal growth factor receptor (EGFR)/PI3K p110α/phosphorylated ribosomal S6 protein (p-S6) was correlated with shorter patient survival. Inhibition of PI3K p110α activity impaired the anchorage-dependent growth of glioblastoma cells and induced tumor regression in vivo. Inhibition of PI3K p110α or PI3K p110β also led to impaired anchorage-independent growth, a decreased migratory capacity of glioblastoma cells, and reduced the activation of the Akt/mTOR pathway. These effects were selective, because targeting of PI3K p110δ did not result in a comparable impairment of glioblastoma tumorigenic properties. Together, our data reveal that drugs targeting PI3K p110α can reduce growth in a subset of glioblastoma tumors characterized by the expression of EGFR/PI3K p110α/p-S6.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Apoptosis / drug effects
Brain Neoplasms / enzymology
Brain Neoplasms / pathology*
Cell Adhesion / drug effects
Cell Division / drug effects
Cell Line, Tumor
Cell Movement / drug effects
Cell Survival / drug effects
Chick Embryo
Class Ia Phosphatidylinositol 3-Kinase / physiology
Drug Screening Assays, Antitumor
Enzyme Induction
Glioblastoma / enzymology
Glioblastoma / pathology*
Humans
Hydrazones / pharmacology
Morpholines / pharmacology
Neoplasm Proteins / antagonists & inhibitors*
Phosphoinositide-3 Kinase Inhibitors*
Protein Kinase Inhibitors / pharmacology*
Proto-Oncogene Proteins c-akt / physiology
RNA Interference
Signal Transduction / drug effects
Substrate Specificity
Sulfonamides / pharmacology
Thiophenes / pharmacology
Tumor Cells, Cultured

Substances

3-(4-morpholinothieno(3,2-d)pyrimidyl-2-yl)phenol
Hydrazones
Morpholines
Neoplasm Proteins
PIK 75
Phosphoinositide-3 Kinase Inhibitors
Protein Kinase Inhibitors
Sulfonamides
Thiophenes
Class Ia Phosphatidylinositol 3-Kinase
AKT1 protein, human
Proto-Oncogene Proteins c-akt

Grants and funding

Oncosuisse (OCS-01501-02-2004); Krebsliga Zürich; European Union’s Seventh Framework Programme (FP7/2007-2013, grant agreement n°259348). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.