Tumor hypoxia has been described to increase the resistance of
cancer cells to
radiation therapy and
chemotherapy. It also supports the invasiveness and metastatic potential of the
tumor. However, few data are available on the transduction pathway set up under
hypoxia and leading to this resistance against anti-
cancer therapies. HIF-1, the main
transcription factor activated by
hypoxia, has been recently shown to participate to this process although its role as an anti- or a
pro-apoptotic protein is still controversy. In this study, we showed that
hypoxia protected HepG2 cells against
etoposide-induced apoptosis. The effect of
hypoxia on cell death was assayed by measuring different parameters of the apoptotic pathway, like DNA fragmentation,
caspase activity and PARP-1 cleavage. The possible implication of HIF-1 in the anti-apoptotic role of
hypoxia was investigated using HIF-1alpha
siRNA. Our results indicated that HIF-1 is not involved in the
hypoxia-induced anti-apoptotic pathway. Another
transcription factor, AP-1, was studied for its potential role in the
hypoxia-induced protection against apoptosis. Specific inhibition of
AP-1 decreased the protection effect of
hypoxia against
etoposide-induced apoptosis. Together, all these data underline that
hypoxia could mediate its anti-apoptotic role via different
transcription factors depending on the cellular context and pro-apoptotic stimuli.