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

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.

journal_name

Oncogene

journal_title

Oncogene

authors

Matteucci E,Modora S,Simone M,Desiderio MA

doi

10.1038/sj.onc.1206519

subject

Has Abstract

pub_date

2003-06-26 00:00:00

pages

4062-73

issue

26

eissn

0950-9232

issn

1476-5594

pii

1206519

journal_volume

22

pub_type

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