caa a22 4500 60549097X CHVBK 20210128100507.0 cr unu---uuuuu 210128e20150601xx s 000 0 eng 10.1007/s10147-014-0734-y doi (NATIONALLICENCE)springer-10.1007/s10147-014-0734-y 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 [Elektronische Daten] [Hiroaki Yazama, Kazuyuki Kitatani, Kazunori Fujiwara, Misaki Kato, Mayumi Hashimoto-Nishimura, Katsuyuki Kawamoto, Kensaku Hasegawa, Hiroya Kitano, Alicja Bielawska, Jacek Bielawski, Toshiro Okazaki] 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 (300mg/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. Japan Society of Clinical Oncology, 2014 Angiogenesis nationallicence Dietary glucosylceramides nationallicence Head and neck cancer nationallicence VEGF nationallicence VEGFR-2 nationallicence HIF-1α nationallicence Yazama Hiroaki Department of Otolaryngology, Head and Neck Surgery, Faculty of Medicine, Tottori University, Nishimachi 86, 683-8503, Yonago, Japan aut Kitatani Kazuyuki Division of Clinical Laboratory Medicine, Faculty of Medicine, Tottori University, Nishimachi 86, 683-8503, Yonago, Japan aut Fujiwara Kazunori Department of Otolaryngology, Head and Neck Surgery, Faculty of Medicine, Tottori University, Nishimachi 86, 683-8503, Yonago, Japan aut Kato Misaki Tottori University Hospital Cancer Center, 683-8504, Yonago, Japan aut Hashimoto-Nishimura Mayumi Tottori University Hospital Cancer Center, 683-8504, Yonago, Japan aut Kawamoto Katsuyuki Department of Otolaryngology, Head and Neck Surgery, Faculty of Medicine, Tottori University, Nishimachi 86, 683-8503, Yonago, Japan aut Hasegawa Kensaku Department of Otolaryngology, Head and Neck Surgery, Faculty of Medicine, Tottori University, Nishimachi 86, 683-8503, Yonago, Japan aut Kitano Hiroya Department of Otolaryngology, Head and Neck Surgery, Faculty of Medicine, Tottori University, Nishimachi 86, 683-8503, Yonago, Japan aut Bielawska Alicja Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 29425, Charleston, USA aut Bielawski Jacek Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 29425, Charleston, USA aut Okazaki Toshiro Division of Hematology and Immunology, Kanazawa Medical University, 920-0293, Uchinada, Japan aut International Journal of Clinical Oncology Springer Japan 20/3(2015-06-01), 438-446 1341-9625 20:3<438 2015 20 10147 https://doi.org/10.1007/s10147-014-0734-y text/html Onlinezugriff via DOI BK010053 XK010053 XK010000 Metadata rights reserved Springer special CC-BY-NC licence nationallicence 1 research-article jats NATIONALLICENCE NATIONALLICENCE NL-springer NATIONALLICENCE 856 40 https://doi.org/10.1007/s10147-014-0734-y text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Yazama Hiroaki Department of Otolaryngology, Head and Neck Surgery, Faculty of Medicine, Tottori University, Nishimachi 86, 683-8503, Yonago, Japan aut NATIONALLICENCE 700 1- Kitatani Kazuyuki Division of Clinical Laboratory Medicine, Faculty of Medicine, Tottori University, Nishimachi 86, 683-8503, Yonago, Japan aut NATIONALLICENCE 700 1- Fujiwara Kazunori Department of Otolaryngology, Head and Neck Surgery, Faculty of Medicine, Tottori University, Nishimachi 86, 683-8503, Yonago, Japan aut NATIONALLICENCE 700 1- Kato Misaki Tottori University Hospital Cancer Center, 683-8504, Yonago, Japan aut NATIONALLICENCE 700 1- Hashimoto-Nishimura Mayumi Tottori University Hospital Cancer Center, 683-8504, Yonago, Japan aut NATIONALLICENCE 700 1- Kawamoto Katsuyuki Department of Otolaryngology, Head and Neck Surgery, Faculty of Medicine, Tottori University, Nishimachi 86, 683-8503, Yonago, Japan aut NATIONALLICENCE 700 1- Hasegawa Kensaku Department of Otolaryngology, Head and Neck Surgery, Faculty of Medicine, Tottori University, Nishimachi 86, 683-8503, Yonago, Japan aut NATIONALLICENCE 700 1- Kitano Hiroya Department of Otolaryngology, Head and Neck Surgery, Faculty of Medicine, Tottori University, Nishimachi 86, 683-8503, Yonago, Japan aut NATIONALLICENCE 700 1- Bielawska Alicja Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 29425, Charleston, USA aut NATIONALLICENCE 700 1- Bielawski Jacek Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 29425, Charleston, USA aut NATIONALLICENCE 700 1- Okazaki Toshiro Division of Hematology and Immunology, Kanazawa Medical University, 920-0293, Uchinada, Japan aut NATIONALLICENCE 773 0- International Journal of Clinical Oncology Springer Japan 20/3(2015-06-01), 438-446 1341-9625 20:3<438 2015 20 10147