Mechanism of HIF-1α-dependent suppression of hypoxia-induced apoptosis in squamous cell carcinoma cells

The transcriptional factor hypoxia-inducible factor-1 (HIF-1) plays an important role in solid tumor cell growth and survival. Overexpression of HIF-1 alpha has been demonstrated in many human tumors and predicts a poor response to chemoradiotherapy. We examined the HIF-1 alpha-induced survival pathways in human oral squamous cell carcinoma cell (OSCC) lines. The results showed that forced expression of HIF-1a suppressed hypoxia-induced apoptosis of OSCC lines by inhibiting cytochrome c release from mitochondria. Overexpression of HIF-1a inhibited the generation of reactive oxygen species (ROS), elevation of intracellular Ca2+ concentration, reduction of mitochondrial membrane potential, and cytosolic accumulation of cytochrome c, which resulted in the inactivation of caspase-9 and caspase-3. In addition, antiapoptotic BcI-2 and BCl-X-L levels were increased and pro-apoptotic Bax and Bak levels were decreased in the HIF-1 alpha-overexpressing OSCC line. Overexpression of HIF-1 alpha also increased the levels of phosphorylation of Akt and extracellular signal-regulated kinases (ERK). These findings indicate that HIF-1a prevents apoptotic cell death through two mechanisms, including inhibition of cytochrome c release and activation of Akt and ERK.