Top

International Journal of Clinical Oncology

Published in:

01-02-2017 | Original Article

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

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

Published in: International Journal of Clinical Oncology | Issue 1/2017

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.

Available only for authorised users

Torre LA, Bray F, Siegel RL et al (2015) Global cancer statistics. CA Cancer J Clin 65(2):87–108. doi: 10.3322/caac.21262

Allenspach EJ, Maillard I, Aster JC et al (2002) Notch signaling in cancer. Cancer Biol Ther 1(5):466–476CrossRefPubMed

Iso T, Kedes L, Hamamori Y (2003) Hes and HERP families: multiple effectors of the Notch signaling pathway. J Cell Physiol 194(3):237–255CrossRefPubMed

Weignmaster G, Kopan R (2006) A garden of Notch-ly delights. Development 133(17):3277–3282CrossRef

Das I, Craig C, Funahashi Y et al (2005) Notch oncoproteins depend on gamma-secretase/presenilin activity processing and function. J Biol Chem 279(29):30771–30780CrossRef

Curry CL, Reed LL, Golde TE et al (2005) Gammma secretase inhibitor blocks Notch activation and induces apoptosis in Kaposi’s sarcoma tumor cells. Oncogene 24(42):6333–6344PubMed

Duechler M, Shehata M, Schwarzmeier JD et al (2005) Induction of apoptosis by proteasome inhibitors in B-CLL cells is associated with down regulation of CD23 and inactivation of Notch2. Leukemia 19(2):260–267CrossRefPubMed

Reedijk M, Odorcic S, Chang L et al (2005) High-level co-expression of JAG1 and NOTCH1 is observed in human breast cancer and is associated with poor overall survival. Cancer Res 65(18):8530–8537CrossRefPubMed

Haruki N, Kawaguchi KS, Eichenberger S et al (2005) Dominant-negative Notch3 receptor inhibits mitogen-activated protein kinase pathway and the growth of human lung cancers. Cancer Res 65(9):3555–3561CrossRefPubMed

10.

Konishi J, Kawaguchi KS, Vo H et al (2007) Gamma-secretase inhibitor prevents Notch3 activation and reduces proliferation in human lung cancers. Cancer Res 67(17):8051–8057CrossRefPubMed

11.

Mizugaki H, Sakakibara-Konishi J, Ikezawa Y et al (2012) γ-Secretase inhibitor enhances sntitumor effect of radiation in Notch-expressing lung cnacer. Br J Cancer 106(12):1953–1959CrossRefPubMedPubMedCentral

12.

Harris AL (2002) Hypoxia—a key regulatory factor in tumor growth. Nature Reviews Cancer 2(1):38–47CrossRefPubMed

13.

Moeller BJ, Dreher MR, Rabbani ZN et al (2005) Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell 8(2):99–110CrossRefPubMed

14.

Moeller BJ, Dewhirst MW (2006) HIF-1 and tumor radiosensitivity. Br J Cancer 95(1):1–5CrossRefPubMedPubMedCentral

15.

Dewhirst MW, Cao Y, Moeller BJ (2008) Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response. Nat Rev 8(6):425–437CrossRef

16.

Gustafsson MV, Zheng X, Pereira T et al (2005) Hypoxia requires notch signaling to maintain the undifferentiated cell state. Development 9(5):617–628

17.

Dang TP, Gazdar AF, Virmani AK et al (2000) Chromosome 19 translocation, overexpression of Notch3, and human lung cancer. J Natl Cancer Inst 92(16):1355–1357CrossRefPubMed

18.

Konishi J, Yi F, Chen X et al (2010) Notch3 cooperates with the EGFR pathway to modulate apoptosis through the induction of bim. Oncogene 29(4):589–596CrossRefPubMed

19.

Chao C (2010) Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Res 70(2):440–446CrossRef

20.

Chao C, Mu Y, Hallahan DE et al (2004) XIAP and surviving as therapeutic targets for radiation sensitization in preclinical models of lung cancer. Oncogene 23(42):7047–7052CrossRef

21.

Yeo EJ, Chun YS, Cho YS et al (2003) YC-1: a potential anticancer drug targeting Hypoxia-Inducible factor 1. J Natl Cancer Inst 95(7):516–525CrossRefPubMed

22.

Yasui H, Ogura A, Asanuma T et al (2008) Inhibition of HIF-1α by the anticancer drug TAS106 enhances X-ray-induced apoptosis in vitro and in vivo. Br J Cancer 99(9):1442–1452CrossRefPubMedPubMedCentral

23.

Moon SY, Chang HW, Roh JL et al (2009) Using YC-1 to overcome the radioresistance of hypoxia cancer cells. Oral Oncol 45(10):915–919CrossRefPubMed

24.

Harada H, Itasaka S, Zhu Y et al (2009) Treatment regimen determines whether an HIF-1α inhibitor enhances or inhibits the effect of radiation therapy. Br J Cancer 100(5):747–757CrossRefPubMedPubMedCentral

25.

Moeller BJ, Richardson RA, Dewhirst MW (2007) Hypoxia and radiotherapy: opportunities for improved outcomes in cancer treatment. Cancer Metastasis Rev 26(2):241–248CrossRefPubMed

26.

Zhu Y, Zhao T, Itasaka S et al (2013) Involvement of decreased hypoxia-inducible factor 1 activity and resultant G1-S cell cycle transition in radiaresistance of perinecrotic tumor cells. Oncogene 32(16):2058–2068CrossRefPubMed

27.

Chen Y, DeMarco MA, Graziani I et al (2007) Oxygen concentration determines the biological effects of NOTCH-1 signaling in adenocarcinoma of the lung. Cancer Res 67(17):7954–7959CrossRefPubMed

28.

Lu X, Kang Y (2010) Hypoxia and hypoxia inducible factors: master regulators of metastasis. Clin Cancer Res 16(24):5298–5935CrossRef

29.

Chen J, Imamura N, Chen H et al (2010) Hypoxia potentiates Notch signaling in breast cancer leading to decreased E-cadherin expression and increase cell migration and invasion. Br J Cancer 102(2):351–360CrossRefPubMed

30.

Sahlgre C, Gustafsson MV, Jin S et al (2008) Notch signaling mediates hypoxia-induced tumor cell migration and invasion. Proc Natl Acad Sci USA 105(17):6392–6397CrossRef

31.

Qiang L, Wu T, Zhang HW et al (2011) HIF-1α is critical for hypoxia-mediated maintenance of glioblastoma cells by activating Notch signaling pathway. Cell Death Differ 19(2):284–294CrossRefPubMedPubMedCentral

32.

Semenza GL, Roth PH, Fang HM et al (1994) Transcriptional regulation of genes encoding glycolytic enzymes by hypoxia inducible factor 1. J Biol Chem 269(38):23757–23763PubMed

33.

Carmeliet P, Dor Y, Herbert JM et al (1998) Role of HIF-1 alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature 394(6692):485–490CrossRefPubMed

34.

Patiar S, Harris AL (2006) Role of hypoxia-inducible factor-1 as a cancer therapy target. Endocr Relat Cancer 13[Suppl 1]:s61–s75CrossRefPubMed

35.

Yan M, Plowman GD (2007) Delta-like 4/Notch signaling and its therapeutic implications. Clin Cancer Res 13(24):7243–7246CrossRefPubMed

36.

Thurston G, Noguera-Troise I, Yancopoulos GD (2007) The Delta paradox: DLL4 blockade leads to more tumour vessels but less tumour growth. Nat Rev 7(5):327–331CrossRef

37.

Thurston G, Kitajewski J (2008) VEGF and Delta-Notch: interacting signaling pathways in tumour angiogenesis. Br J Cancer 99(8):1204–1209CrossRefPubMedPubMedCentral

Title: Inhibition of Notch and HIF enhances the antitumor effect of radiation in Notch expressing lung cancer
Authors: Yasuyuki Ikezawa
Jun Sakakibara-Konishi
Hidenori Mizugaki
Satoshi Oizumi
Masaharu Nishimura
Publication date: 01-02-2017
Publisher: Springer Japan
Published in: International Journal of Clinical Oncology / Issue 1/2017
Print ISSN: 1341-9625
Electronic ISSN: 1437-7772
DOI: https://doi.org/10.1007/s10147-016-1031-8

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Result

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2017

One-step nucleic acid amplification (OSNA): where do we go with it?

A phase III multicenter, randomized, controlled study of combined androgen blockade with versus without zoledronic acid in prostate cancer patients with metastatic bone disease: results of the ZAPCA trial

Japanese contribution to the field of sentinel lymph node biopsy for breast cancer patients: introduction to invited articles

The role of periodic serum CA19-9 test in surveillance after colorectal cancer surgery

Psychological impact of positive cervical cancer screening results among Japanese women

Expression of p53, p16, cyclin D1, epidermal growth factor receptor and Notch1 in patients with temporal bone squamous cell carcinoma

Keynote webinar | Spotlight on antibody–drug conjugates in cancer