Hepatocyte growth factor induces apoptosis through the extrinsic pathway in hepatoma cells: favouring role of hypoxia-inducible factor-1 deficiency

Oncogene. 2003 Jun 26;22(26):4062-73. doi: 10.1038/sj.onc.1206519.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis*
  • Blotting, Northern
  • Blotting, Western
  • Cadherins / metabolism
  • Carcinoma, Hepatocellular / metabolism*
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases / metabolism
  • Cell Death
  • Cytochrome c Group / metabolism
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / physiology*
  • Densitometry
  • Enzyme Activation
  • Genetic Vectors
  • Hepatocyte Growth Factor / metabolism*
  • Humans
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Mitochondria / metabolism
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinases / metabolism
  • Mutation
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / physiology*
  • Proto-Oncogene Proteins c-met
  • Proto-Oncogene Proteins*
  • Receptors, Growth Factor*
  • Scattering, Radiation
  • Time Factors
  • Trans-Activators / metabolism
  • Transcription Factors*
  • Tumor Cells, Cultured

Substances

  • Cadherins
  • Cytochrome c Group
  • DNA-Binding Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Receptors, Growth Factor
  • Trans-Activators
  • Transcription Factors
  • Hepatocyte Growth Factor
  • MET protein, human
  • Proto-Oncogene Proteins c-met
  • Mitogen-Activated Protein Kinase 8
  • Mitogen-Activated Protein Kinases
  • CASP3 protein, human
  • CASP8 protein, human
  • CASP9 protein, human
  • Caspase 3
  • Caspase 8
  • Caspase 9
  • Caspases