Targeting class IA PI3K isoforms selectively impairs cell growth, survival, and migration in glioblastoma.
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.
Department of Clinical Research, University of Bern, Bern, Switzerland.
Katrin
K
Höland
Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland.
Danielle
D
Boller
Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
Christian
C
Hagel
Department of Neurosurgery, University Hospital Zurich, Zurich, Switzerland.
Silvia
S
Dolski
Department of Medical Biometry and Epidemiology, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
András
A
Treszl
Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
Olivier E
OE
Pardo
Department of Clinical Research, University of Bern, Bern, Switzerland.
Paulina
P
Cwiek
Department of Clinical Research, University of Bern, Bern, Switzerland.
Fabiana
F
Salm
Department of Clinical Research, University of Bern, Bern, Switzerland.
Zaira
Z
Leni
Department of Molecular Medicine and Pathology, University of Auckland, Auckland, New Zealand.
Peter R
PR
Shepherd
Institute of Anatomy, University of Bern, Bern, Switzerland.
Beata
B
Styp-Rekowska
Institute of Anatomy, University of Bern, Bern, Switzerland.
Valentin
V
Djonov
Division of Pediatric Hematology and Oncology, Department of Pediatrics and Adolescent Medicine, University Medical Center Goettingen, Goettingen, Germany.
André O
AO
von Bueren
Department of Neurosurgery, University Hospital Zurich, Zurich, Switzerland.
Karl
K
Frei
Department of Clinical Research, University of Bern, Bern, Switzerland; Division of Clinical Chemistry and Biochemistry, University Children's Hospital Zurich, Zurich, Switzerland.
Alexandre
A
Arcaro
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000201:enzymology / Q000473:pathology*; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002642:Chick Embryo; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000502:physiology; D004354:Drug Screening Assays, Antitumor; D004790:Enzyme Induction; D005909:Glioblastoma / Q000201:enzymology / Q000473:pathology*; D006801:Humans; D006835:Hydrazones / Q000494:pharmacology; D009025:Morpholines / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology; D034622:RNA Interference; D015398:Signal Transduction / Q000187:drug effects; D013379:Substrate Specificity; D013449:Sulfonamides / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology; D014407:Tumor Cells, Cultured
C000598597:3-(4-morpholinothieno(3,2-d)pyrimidyl-2-yl)phenol; D006835:Hydrazones; D009025:Morpholines; D009363:Neoplasm Proteins; C549211:PIK 75; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D013876:Thiophenes; D058543:Class Ia Phosphatidylinositol 3-Kinase; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt