Hepatocyte growth factor sensitizes human ovarian carcinoma cell lines to paclitaxel and cisplatin.
The hepatocyte growth factor (HGF) receptor, encoded by the MET oncogene, is expressed in approximately 70% of human ovarian carcinomas and overexpressed in 30% of cases. Because HGF is known to protect cells from apoptosis, we investigated whether receptor expression modifies ovarian cancer cell response to chemotherapy. The apoptotic effect of the front-line chemotherapeutic drugs paclitaxel and cisplatin on cells treated with HGF was studied. In ovarian cancer cell lines, pretreatment with HGF surprisingly enhances the apoptotic response to low doses of paclitaxel and cisplatin. HGF empowers specifically the intrinsic apoptotic pathway, whereas it protects cells from extrinsic Fas-induced apoptosis. Chemotherapy sensitization is specific for HGF because another growth factor (e.g., epidermal growth factor) increases ovarian cancer cell survival. In nonovarian cancer cell models, as expected, HGF provides protection from drug-induced apoptosis. These data show that HGF sensitizes ovarian carcinoma cells to low-dose chemotherapeutic agents. This suggests that HGF may be used to improve response to chemotherapy in a set of human ovarian carcinomas molecularly classified based on the MET oncogene expression.
Rasola
Andrea
A
Division of Molecular Oncology, Institute for Cancer Research and Treatment, University of Torino Medical School, Candiolo, Italy. andrea.rasola@ircc.it
Anguissola
Sergio
S
Ferrero
Norma
N
Gramaglia
Daniela
D
Maffe
Antonella
A
Maggiora
Piera
P
Comoglio
Paolo M
PM
Di Renzo
M Flavia
MF
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000502:physiology; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D005260:Female; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D009687:Nuclear Proteins / Q000502:physiology; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000473:pathology; D017239:Paclitaxel / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D000097642:GADD45 Proteins
D000970:Antineoplastic Agents; D020169:Caspases; D018797:Cell Cycle Proteins; D002945:Cisplatin; D017228:Hepatocyte Growth Factor; D009687:Nuclear Proteins; D017239:Paclitaxel; C439070:GADD45A protein, human; D000097642:GADD45 Proteins