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Dietary glucosylceramides suppress tumor growth in a mouse xenograft model of head and neck squamous cell carcinoma by the inhibition of angiogenesis through an increase in ceramide

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Abstract

Background

We previously reported that dietary glucosylceramides show cancer-prevention activity in a mouse xenograft model of human head and neck cancer cells (SCCKN). However, the mechanism was unclear. Ceramides, metabolites of glucosylceramides, induce apoptotic cell death in various malignancies. Here, we investigated the inhibitory effects of dietary glucosylceramides on tumor growth in vivo and in vitro.

Methods

SCCKN were subcutaneously inoculated into the right flanks of NOD/SCID mice. Mice were treated with or without dietary glucosylceramides (300 mg/kg) daily for 14 consecutive days after confirmation of tumor progression. Microvessel areas around the tumor were assessed by hematoxylin–eosin staining and immunohistochemistry of CD31, and, as markers for angiogenesis, protein levels of VEGF, VEGF receptor-2, and HIF-1α were assessed by Western blotting. Mass spectrometry was performed to measure the levels of sphingolipids in mouse serum after treatment with dietary glucosylceramides.

Results

Oral administration of glucosylceramides significantly decreased SCCKN growth in the xenograft model with inhibition of angioinvasion. In tumor-invasive areas, VEGF and HIF-1α in the tumor cells, and VEGF receptor-2 in endothelial cells decreased after treatment with dietary glucosylceramides. Dietary glucosylceramides increased serum levels of sphingosine-based ceramides as compared to the control. In SCCKN and UV♀2 cells, C6-ceramide suppressed the expressions of VEGF, VEGF receptor-2, and HIF-1α in vitro.

Conclusion

These results suggest that dietary glucosylceramides trigger the de novo pathway of ceramide synthesis, indicating that sphingosine-based ceramide suppresses the growth of head and neck tumors through the inhibition of pro-angiogenic signals such as VEGF, VEGF receptor-2, and HIF-1α.

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Acknowledgments

This work was partly supported by Takeda Science Foundation and performed under a joint research project with Shalome Co. Ltd. and Ono Pharmaceutical Co. Ltd. This study was supported in part by a grant of the Strategic Research Foundation Grant-aided Project for Private Universities from the Ministry of Education, Culture, Sport, Science, and Technology, Japan (MEXT) (No. S1201004) from Kanazawa Medical University (H2012-15), 2012-2016, from the SENSHIN Medical Research Foundation, from the Mizutani Foundation for Glycoscience; from the Collaborative Research from Kanazawa Medical University (C2012-4, C2013-1); and from the Chieko Sakurai Commemorative Grant.

Conflict of interest

They have no conflict of interest.

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Authors and Affiliations

  1. Department of Otolaryngology, Head and Neck Surgery, Faculty of Medicine, Tottori University, Nishimachi 86, Yonago, 683-8503, Japan

    Hiroaki Yazama, Kazunori Fujiwara, Katsuyuki Kawamoto, Kensaku Hasegawa & Hiroya Kitano

  2. Division of Clinical Laboratory Medicine, Faculty of Medicine, Tottori University, Nishimachi 86, Yonago, 683-8503, Japan

    Kazuyuki Kitatani

  3. Tottori University Hospital Cancer Center, Yonago, 683-8504, Japan

    Misaki Kato & Mayumi Hashimoto-Nishimura

  4. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, 29425, USA

    Alicja Bielawska & Jacek Bielawski

  5. Division of Hematology and Immunology, Kanazawa Medical University, Uchinada, 920-0293, Japan

    Toshiro Okazaki

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  1. Hiroaki Yazama
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  2. Kazuyuki Kitatani
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Correspondence to Toshiro Okazaki.

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Yazama, H., Kitatani, K., Fujiwara, K. et al. Dietary glucosylceramides suppress tumor growth in a mouse xenograft model of head and neck squamous cell carcinoma by the inhibition of angiogenesis through an increase in ceramide. Int J Clin Oncol 20, 438–446 (2015). https://doi.org/10.1007/s10147-014-0734-y

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  • DOI: https://doi.org/10.1007/s10147-014-0734-y

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