Prevention of irradiation-induced glioma cell invasion by temozolomide involves caspase 3 activity and cleavage of focal adhesion kinase.
Sublethal doses of irradiation enhance the invasiveness of human malignantglioma cells. This can be inhibited by subtoxic concentrations of temozolomide (TMZ) but not by lomustine. Antagonism of irradiation-induced motility by TMZ is associated with the prevention of irradiation-induced alpha(v)beta(3)-integrin, matrix metalloproteinase-2 and MT1-matrix metalloproteinase-expression. Irradiation induces focal adhesion kinase (FAK) activation by phosphorylation, whereas TMZ promotes FAK cleavage. Inhibition of caspases prevents TMZ-induced FAK processing and restores the promigratory effect of irradiation, suggesting that the resistance of glioma cells to irradiation-induced caspase processing may determine the invasive responses of glioma cells to irradiation. In contrast, DAOY medulloblastoma cells, which respond with caspase activation to irradiation alone, do not show enhanced invasiveness when irradiated.
Wick
Wolfgang
W
Laboratories of Molecular Neuro-Oncology, University of Tübingen, Medical School, D-72076 Tübingen, Germany. wolfgang.wick@uni-tuebingen.de
Wick
Antje
A
Schulz
Jörg B
JB
Dichgans
Johannes
J
Rodemann
Hans P
HP
Weller
Michael
M
D016475:3T3 Cells; D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology*; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D003131:Combined Modality Therapy; D003606:Dacarbazine / Q000031:analogs & derivatives / Q000494:pharmacology*; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005910:Glioma / Q000188:drug therapy / Q000201:enzymology* / Q000473:pathology* / Q000532:radiotherapy; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D061965:Matrix Metalloproteinase Inhibitors; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D051379:Mice; D009361:Neoplasm Invasiveness; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D019030:Receptors, Vitronectin / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D000077204:Temozolomide; D014407:Tumor Cells, Cultured; D015854:Up-Regulation / Q000187:drug effects
D018906:Antineoplastic Agents, Alkylating; D061965:Matrix Metalloproteinase Inhibitors; D019030:Receptors, Vitronectin; D003606:Dacarbazine; D011505:Protein-Tyrosine Kinases; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C496050:PTK2 protein, human; C496051:Ptk2 protein, mouse; C496052:Ptk2 protein, rat; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D020778:Matrix Metalloproteinase 2; D000077204:Temozolomide