Imatinib and Nilotinib increase glioblastoma cell invasion via Abl-independent stimulation of p130Cas and FAK signalling.
Imatinib was the first targeted tyrosine kinase inhibitor to be approved for clinical use, and remains first-line therapy for Philadelphia chromosome (Ph+)-positive chronic myelogenous leukaemia. We show that treatment of human glioblastoma multiforme (GBM) tumour cells with imatinib and the closely-related drug, nilotinib, strikingly increases tyrosine phosphorylation of p130Cas, focal adhesion kinase (FAK) and the downstream adaptor protein paxillin (PXN), resulting in enhanced cell migration and invasion. Imatinib and nilotinib-induced tyrosine phosphorylation was dependent on expression of p130Cas and FAK activity and was independent of known imatinib targets including Abl, platelet derived growth factor receptor beta (PDGFRβ) and the collagen receptor DDR1. Imatinib and nilotinib treatment increased two dimensional cell migration and three dimensional radial spheroid invasion in collagen. In addition, silencing of p130Cas and inhibition of FAK activity both strongly reduced imatinib and nilotinib stimulated invasion. Importantly, imatinib and nilotinib increased tyrosine phosphorylation of p130Cas, FAK, PXN and radial spheroid invasion in stem cell lines isolated from human glioma biopsies. These findings identify a novel mechanism of action in GBM cells for two well established front line therapies for cancer resulting in enhanced tumour cell motility.
Centre for Cardiovascular Biology and Medicine, Division of Medicine, The Rayne Building, London WC1E 6JJ, United Kingdom.
Antonina
A
Frolov
Centre for Cardiovascular Biology and Medicine, Division of Medicine, The Rayne Building, London WC1E 6JJ, United Kingdom.
Ian M
IM
Evans
Division of Neuropathology, Institute of Neurology, London WC1E 6JJ, United Kingdom.
Ningning
N
Li
Division of Neuropathology, Institute of Neurology, London WC1E 6JJ, United Kingdom.
Kastytis
K
Sidlauskas
Centre for Cardiovascular Biology and Medicine, Division of Medicine, The Rayne Building, London WC1E 6JJ, United Kingdom.
Ketevan
K
Paliashvili
Centre for Cardiovascular Biology and Medicine, Division of Medicine, The Rayne Building, London WC1E 6JJ, United Kingdom.|UCL COMPLEX, University College London, London WC1E 6JJ, United Kingdom.
Nicola
N
Lockwood
Centre for Cardiovascular Biology and Medicine, Division of Medicine, The Rayne Building, London WC1E 6JJ, United Kingdom.
Angela
A
Barrett
Division of Neuropathology, Institute of Neurology, London WC1E 6JJ, United Kingdom.
Sebastian
S
Brandner
Centre for Cardiovascular Biology and Medicine, Division of Medicine, The Rayne Building, London WC1E 6JJ, United Kingdom.
Ian C
IC
Zachary
Centre for Cardiovascular Biology and Medicine, Division of Medicine, The Rayne Building, London WC1E 6JJ, United Kingdom.
Paul
P
Frankel
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D050719:Crk-Associated Substrate Protein / Q000378:metabolism*; D000070819:Discoidin Domain Receptor 1 / Q000378:metabolism; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D000068877:Imatinib Mesylate / Q000494:pharmacology*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy / Q000378:metabolism; D009361:Neoplasm Invasiveness / Q000473:pathology*; D051419:Paxillin / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D048868:Adaptor Proteins, Signal Transducing; C493841:BCAR1 protein, human; D050719:Crk-Associated Substrate Protein; D051419:Paxillin; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D000070819:Discoidin Domain Receptor 1; D020797:Receptor, Platelet-Derived Growth Factor beta; D051417:Focal Adhesion Kinase 1; C496050:PTK2 protein, human; D016315:Proto-Oncogene Proteins c-abl; C498826:nilotinib