Abstract
Two hepatocarcinoma cell lines, the Hepa-1 wild-type (c1c7) and the β-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-1β 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.
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Acknowledgements
This work was supported by grants from the Consiglio Nazionale delle Ricerche (C.N.R.), Associazione Italiana per la Ricerca sul Cancro (A.I.R.C.) and Ministero dell'Università e della Ricerca Scientifica e Tecnologica – Italy. We thank Dr O Hankinson, who kindly provided wild-type, mutated and stably transfected Hepa-1 cells.
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Matteucci, E., Modora, S., Simone, M. et al. Hepatocyte growth factor induces apoptosis through the extrinsic pathway in hepatoma cells: favouring role of hypoxia-inducible factor-1 deficiency. Oncogene 22, 4062–4073 (2003). https://doi.org/10.1038/sj.onc.1206519
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DOI: https://doi.org/10.1038/sj.onc.1206519
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