1. The involvement of hypoxia-inducible factor-1alpha in the susceptibility to gamma-rays and chemotherapeutic drugs of oral squamous cell carcinoma cells.
- Author
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Sasabe E, Zhou X, Li D, Oku N, Yamamoto T, and Osaki T
- Subjects
- ATP Binding Cassette Transporter, Subfamily B, Member 1 genetics, Antineoplastic Agents therapeutic use, Carcinoma, Squamous Cell drug therapy, Carcinoma, Squamous Cell radiotherapy, Cell Line, Tumor, Ceruloplasmin genetics, Ceruloplasmin metabolism, Cisplatin therapeutic use, Fluorouracil therapeutic use, Gamma Rays, Heme Oxygenase-1 genetics, Heme Oxygenase-1 metabolism, Humans, Hypoxia-Inducible Factor 1, alpha Subunit antagonists & inhibitors, Hypoxia-Inducible Factor 1, alpha Subunit genetics, Mouth Neoplasms drug therapy, Mouth Neoplasms radiotherapy, Promoter Regions, Genetic genetics, RNA, Small Interfering genetics, RNA, Small Interfering pharmacology, Reactive Oxygen Species metabolism, Superoxide Dismutase metabolism, Carcinoma, Squamous Cell therapy, Drug Resistance, Neoplasm genetics, Hypoxia-Inducible Factor 1, alpha Subunit physiology, Mouth Neoplasms therapy, Radiation Tolerance genetics
- Abstract
The transcription factor hypoxia-inducible factor-1alpha (HIF-1alpha) is the key regulator that controls the hypoxic response of mammalian cells. The overexpression of HIF-1alpha has been demonstrated in many human tumors. However, the role of HIF-1alpha in the therapeutic efficacy of chemotherapy and radiotherapy in cancer cells is poorly understood. In this study, we investigated the influence of HIF-1alpha 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-1alpha, and the susceptibility of OSCC cells to the drugs and gamma-rays was negatively correlated with the expression level of HIF-1alpha protein. The overexpression of HIF-1alpha induced OSCC cells to become more resistant to the anticancer agents, and down-regulation of HIF-1alpha expression by small interfering RNA enhanced the susceptibility of OSCC cells to them. In the HIF-1alpha-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-1alpha expression is related to the resistance of tumor cells to chemo- and radio-therapy and that HIF-1alpha is an effective therapeutic target for cancer treatment., ((c) 2006 Wiley-Liss, Inc.)
- Published
- 2007
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