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

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Title: Inhibition of Notch and HIF enhances the antitumor effect of radiation in Notch expressing lung cancer
Authors: Ikezawa, Yasuyuki Browse this author
Sakakibara-Konishi, Jun Browse this author →KAKEN DB
Mizugaki, Hidenori Browse this author
Oizumi, Satoshi Browse this author →KAKEN DB
Nishimura, Masaharu Browse this author →KAKEN DB
Keywords: Notch
Lung cancer
Issue Date: Feb-2017
Publisher: Springer
Journal Title: International Journal of Clinical Oncology
Volume: 22
Issue: 1
Start Page: 59
End Page: 69
Publisher DOI: 10.1007/s10147-016-1031-8
PMID: 27553958
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.
Rights: The final publication is available at Springer via
Type: article (author version)
Appears in Collections:北海道大学病院 (Hokkaido University Hospital) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 榊原 純

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