• Open Access

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

Authors

  • Eri Sasabe,

    Corresponding author
    1. Department of Oral Oncology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku-city, Kochi 783-8505, Japan
      To whom correspondence should be addressed. E-mail: yoshieri@kochi-ms.ac.jp
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  • Yukihiro Tatemoto,

    1. Department of Oral Oncology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku-city, Kochi 783-8505, Japan
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  • Dechao Li,

    1. Department of Oral Oncology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku-city, Kochi 783-8505, Japan
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  • Tetsuya Yamamoto,

    1. Department of Oral Oncology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku-city, Kochi 783-8505, Japan
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  • Tokio Osaki

    1. Department of Oral Oncology, Kochi Medical School, Kochi University, Kohasu, Oko-cho, Nankoku-city, Kochi 783-8505, Japan
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To whom correspondence should be addressed. E-mail: yoshieri@kochi-ms.ac.jp

Abstract

The transcriptional factor hypoxia-inducible factor-1 (HIF-1) plays an important role in solid tumor cell growth and survival. Overexpression 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 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. Overexpression of HIF-1α 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 Bcl-2 and Bcl-XL levels were increased and pro-apoptotic Bax and Bak levels were decreased in the HIF-1α-overexpressing OSCC line. Overexpression 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. (Cancer Sci 2005; 96: 394–402)

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