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

Ikezawa, Yasuyuki; Sakakibara-Konishi, Jun; Mizugaki, Hidenori; Oizumi, Satoshi; Nishimura, Masaharu

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

Ikezawa, Yasuyuki; Sakakibara-Konishi, Jun; Mizugaki, Hidenori et al.

International Journal of Clinical Oncology, 2017, 22(1), 59-69

Permalink : https://hdl.handle.net/2115/68251

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アクセス権	open access
URI	https://hdl.handle.net/2115/68251
タイトル	Inhibition of Notch and HIF enhances the antitumor effect of radiation in Notch expressing lung cancer
著者	Ikezawa, Yasuyuki ; Sakakibara-Konishi, Jun ; Mizugaki, Hidenori ; Oizumi, Satoshi ; Nishimura, Masaharu
著者名 Ikezawa, Yasuyuki
e-Rad_Researcher 50374278 著者名 Sakakibara-Konishi, Jun
著者名 Mizugaki, Hidenori
e-Rad_Researcher 10421968 著者名 Oizumi, Satoshi
e-Rad_Researcher 00208224 著者名 Nishimura, Masaharu
言語	英語
キーワード	Notch
	HIF-1
	Hypoxia
	Radiosensitivity
	Lung cancer
発行日	2017-02
出版者	Springer
収録物名	International Journal of Clinical Oncology
巻(号)	22(1)
ページ	59-69
抄録	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.
資源タイプ	学術雑誌論文
出版タイプ	Accepted Manuscript
権利情報	The final publication is available at Springer via http://dx.doi.org/10.1007/s10147-016-1031-8
PISSN	1341-9625
関連情報	PMID 27553958
関連情報 (isVersionOf)	出版社版DOI https://doi.org/10.1007/s10147-016-1031-8