The involvement of hypoxia-inducible factor-1α in the susceptibility to γ-rays and chemotherapeutic drugs of oral squamous cell carcinoma cells

The transcription factor hypoxia-inducible factor-1 alpha (HIF-1 alpha) is the key regulator that controls the hypoxic response of mammalian cells. The overexpression of HIF-1 alpha has been demonstrated in many human tumors. However, the role of HIF-1 alpha in the therapeutic efficacy of chemotherapy and radiotherapy in cancer cells is poorly understood. In this study, we investigated the influence of HIF-1 alpha expression on the susceptibility of oral squamous cell carcinoma (OSCC) cells to chemotherapeutic drugs (cis-diamminedichloroplatinum and 5-fluorouracil) and gamma-rays. Treatment with chemotherapeutic drugs and gamma-rays enhanced the expression and nuclear translocation of HIF-1 alpha, and the susceptibility of OSCC cells to the drugs and gamma-rays was negatively correlated with the expression level of HIF-1 alpha protein. The overexpression of HIF-1 alpha induced OSCC cells to become more resistant to the anticancer agents, and down-regulation of HIF-1 alpha expression by small interfering RNA enhanced the susceptibility of OSCC cells to them. In the HIF-1 alpha-knockdown OSCC cells, the expression of P-glycoprotein, heme oxygenase-1, manganese-superoxide dismutase and ceruloplasmin were downregulated 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 enhanced HIF-1 alpha expression is related to the resistance of tumor cells to chemo- and radio-therapy and that HIF-1 alpha is an effective therapeutic target for cancer treatment. (c) 2006 Wiley-Liss, Inc.