International Journal of Clinical Oncology

, Volume 22, Issue 1, pp 59–69 | Cite as

Inhibition of Notch and HIF enhances the antitumor effect of radiation in Notch expressing lung cancer

  • Yasuyuki Ikezawa
  • Jun Sakakibara-Konishi
  • Hidenori Mizugaki
  • Satoshi Oizumi
  • Masaharu Nishimura
Original Article

Abstract

Background

The Notch receptor plays an important role in various cell fate decisions during development and in cancer. We have previously reported that Notch3 is upregulated by radiation in non-small cell lung cancer (NSCLC) cell lines and that the Notch pathway inhibitor γ secretase inhibitor GSI (gamma-secretase inhibitor), when combined with radiation therapy, significantly suppressed the growth of lung cancer cells. However, little is known about the mechanism of Notch upregulation induced by radiation. Based on reports of Notch expression being activated through the hypoxia inducible factor 1 (HIF-1) under hypoxic conditions, we hypothesized that HIF-1 would be involved in radiation-induced Notch activation in NSCLC.

Methods

Changes in HIF-1 and Notch expression in two Notch expressing NSCLC cells line after radiation treatment were examined using Western blotting. Notch expression was evaluated after the suppression of HIF-1α by small interfering RNA. The cytotoxic effect of YC-1, a HIF inhibitor, GSI and radiation was examined using the MTT assay in vitro and the xenograft model.

Result

We found radiation-induced expression of HIF-1α protein at 2–6 h after treatment and upregulated expression of Notch3 protein at 24 h after treatment under hypoxic conditions. Specific suppression of HIF-1α expression downregulated the radiation-induced Notch3 activation, suggesting that the Notch pathway is activated though HIF-1α after radiation. An antitumor effect of YC-1 was evident under hypoxic conditions only when there was simultaneous radiation treatment. GSI and YC-1 had a synergistic antitumor effect in vitro, and the combination of GSI and YC-1 showed the greatest radiosensitivity in vivo.

Conclusion

Radiation-induced upregulation of the Notch pathway and HIF-1α protein may be potential therapeutic targets for more effective radiation therapy.

Keywords

Notch HIF-1 Hypoxia Radiosensitivity Lung cancer 

Supplementary material

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Supplementary material 1 (PPTX 990 kb)
10147_2016_1031_MOESM2_ESM.pptx (626 kb)
Supplementary material 2 (PPTX 626 kb)
10147_2016_1031_MOESM3_ESM.pptx (417 kb)
Supplementary material 3 (PPTX 417 kb)

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Copyright information

© Japan Society of Clinical Oncology 2016

Authors and Affiliations

  • Yasuyuki Ikezawa
    • 1
  • Jun Sakakibara-Konishi
    • 1
  • Hidenori Mizugaki
    • 1
  • Satoshi Oizumi
    • 1
  • Masaharu Nishimura
    • 1
  1. 1.First Department of MedicineHokkaido University School of MedicineKita-ku, SapporoJapan

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