The mechanism of escape from hypoxia-induced apoptosis in squamous cell carcinoma cells.

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The transcription factor hypoxia-inducible factor 1(HIF-1) plays an important role in solid tumor cell growth and survival. Over-expression of HIF-1α has been demonstrated in many human tumors and predicts a poor response to chemoradiotherapy. We examined the HIF-1α-induced survival pathways and the influence of HIF-1α on the susceptibility to chemotherapeutic drugs and γ-rays in human oral squamous cell carcinoma cell (OSCC) lines. The results showed that forced expression of HIF-1α suppressed hypoxia-induced apoptosis of OSCC lines by inhibiting cytochrome c release from mitochondria. Over-expression of HIF-1α inhibited the generation of reactive oxygen species (ROS), elevation of intracellular Ca^<2+> 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, anti-apoptotic Bcl-2 and Bcl-X_L levels were increased and pro-apoptotic Bax and Bak levels were decreas … More ed in the HIF-1α-overexpressing OSCC line. Over-expression of HIF-1α also increased the levels of phosphorylation of Akt and extracellular signal-regulated kinases (ERK). These findings indicate that HIF-1α prevents apoptotic cell death through two mechanisms including inhibition of cytochrome c release and activation of Akt and ERK. Treatment with chemotherapeutic drugs and γ-rays enhanced the expression and nuclear translocation of HIF-1α and the susceptibility of OSCC cells to the drugs and γ-rays was negatively correlated with the expression level of HIF-1α protein. The over-expression of HIF-1α induced OSCC cells more resistant to the anticancer agents and the down-regulation of HIF-1α expression by small interfering RNA enhanced the susceptibility of OSCC cells to them. In the HIF-1α-knockdown OSCC cells, the expression of P-glycoprotein, heme oxygenase-1, manganese-superoxide dismutase and ceruloplasmin were down-regulated and the intracellular levels of chemotherapeutic drugs and reactive oxygen species were sustained at higher levels after the treatment with the anticancer agents. These results suggest that down-regulation of HIF-1α expression is an effective strategy for cancer treatment. Less