Hypoxia protects HepG2 cells against etoposide-induced apoptosis VIA a HIF-1-independent pathway

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-1α
siRNA. Our results indicated that HIF-1 is not involved in the hypoxia-induced antiapoptotic
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.