Hepatocyte growth factor induces apoptosis through the extrinsic pathway in hepatoma cells: favouring role of hypoxia-inducible factor-1 deficiency.
Two hepatocarcinoma cell lines, the Hepa-1 wild-type (c1c7) and the beta-subunit mutated (c4) lacking hypoxia-inducible factor-1 (HIF-1) activity, were differentially susceptible to apoptosis by hepatocyte growth factor (HGF). The c4 cells were 40% apoptotic 48 h after HGF treatment. On the contrary, the wild-type c1c7 cells showed modest signs of apoptosis only at 72 h. The revertant vT[2] cells, consisting of c4 cells stably transfected with HIF-1beta expression vector, behaved as the parental cells. To understand the mechanisms of this different sensitivity, we examined a panel of genes involved in apoptosis: ornithine decarboxylase, c-Myc and p53 protein levels progressively decreased while JNK1, caspase 8 and 3 activities persistently increased in c4 cells undergoing apoptosis. Distinct time-related events in c1c7 cells were the transient activations of JNK1 and caspase 8 followed by the accumulation of ODC and c-Myc proteins. The proapoptotic effect of HGF in c4 hepatocarcinoma cells seems to be related to HIF-1 deficiency with loss of cytoprotective and signalling functions. This may contribute to the triggering of the extrinsic pathway consisting in caspase 8 activation, which in turn causes BID cleavage and cytochrome c release. The effector caspase 3 is also activated.
Matteucci
Emanuela
E
Institute of General Pathology, School of Medicine, University of Milano, via L. Mangiagalli, 31-20133 Milano, Italy.
Modora
Silvia
S
Simone
Matteo
M
Desiderio
Maria Alfonsina
MA
D017209:Apoptosis; D015152:Blotting, Northern; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism*; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D016923:Cell Death; D003574:Cytochrome c Group / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000502:physiology*; D003720:Densitometry; D004789:Enzyme Activation; D005822:Genetic Vectors; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008928:Mitochondria / Q000378:metabolism; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics* / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D019859:Proto-Oncogene Proteins c-met; D017978:Receptors, Growth Factor; D012542:Scattering, Radiation; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors; D014407:Tumor Cells, Cultured
D015820:Cadherins; D003574:Cytochrome c Group; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D017978:Receptors, Growth Factor; D015534:Trans-Activators; D014157:Transcription Factors; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D048055:Mitogen-Activated Protein Kinase 8; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases