Tissue factor mediates the HGF/Met-induced anti-apoptotic pathway in DAOY medulloblastoma cells.
The classical treatment scheme for medulloblastoma (MB) is based on a tri-therapy approach consisting of surgical tumor resection, craniospinal axis radiation and chemotherapy. With current treatments relying mainly on non-specific cytotoxic therapy, a better understanding of the mechanisms underlying resistance to these treatments is important in order to improve their effectiveness. In this study, we report that stimulation of DAOY with HGF resulted in the protection of these cells against etoposide-induced apoptosis, this anti-apoptotic effect being correlated with an increase in the expression of tissue factor (TF), the initiator of the extrinsic pathway of coagulation. HGF-mediated protection from apoptosis was abolished by a c-Met inhibitor as well as by siRNA-mediated reduction of TF levels, implying a central role of Met-dependent induction of TF expression in this process. Accordingly, stimulation of DAOY with FVIIa, the physiological ligand of TF, also resulted in a significant protection from etoposide-mediated cytotoxicity. Overall, our results suggest the participation of the haemostatic system to drug resistance in MB and may thus provide novel therapeutic approaches for the treatment of these tumors.
Provençal
Mathieu
M
Laboratoire de Médecine Moléculaire, Université du Québec à Montréal, CP 8888, Succ Centre-ville, Montreal, QC H3C 3P8, Canada. m.provencal@umontreal.ca
Berger-Thibault
Nancy
N
Labbé
David
D
Veitch
Ryan
R
Boivin
Dominique
D
Rivard
Georges-Etienne
GE
Gingras
Denis
D
Béliveau
Richard
R
D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005047:Etoposide / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D008527:Medulloblastoma / Q000473:pathology; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D051560:Proto-Oncogene Proteins c-bcl-6 / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000077022:Survivin; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection / Q000379:methods; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; C107489:BIRC5 protein, human; C066855:HGF protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D051560:Proto-Oncogene Proteins c-bcl-6; D034741:RNA, Small Interfering; D000077022:Survivin; D016159:Tumor Suppressor Protein p53; D017228:Hepatocyte Growth Factor; D005047:Etoposide; D013925:Thromboplastin; D019859:Proto-Oncogene Proteins c-met; D053148:Caspase 3