Sialyllactose suppresses angiogenesis by inhibiting VEGFR-2 activation, and tumor progression
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Tae-Wook Chung1, Eun-Young Kim1,2, Seok-Jo Kim3, Hee-Jung Choi1, Se Bok Jang4, Keuk-Jun Kim5, Sun-Hyung Ha3, Fukushi Abekura3, Choong-Hwan Kwak3, Cheorl-Ho Kim3 and Ki-Tae Ha1,2
1School of Korean Medicine, Healthy Aging Korean Medical Research Center, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
2Graduate Training Program of Korean Medicine for Healthy-Aging, Pusan National University, Yangsan, Gyeongsangnam-do 50612, Republic of Korea
3Department of Biological Science, Sungkyunkwan University, Suwon, Kyunggi-do 16419, Republic of Korea
4Department of Molecular Biology, College of Natural Sciences, Pusan National University, Geumjeong-gu, Busan 46241, Republic of Korea
5Department of Clinical Pathology, TaeKyeung University, Gyeongsan 38547, Republic of Korea
Cheorl-Ho Kim, email: email@example.com
Ki-Tae Ha, email: firstname.lastname@example.org
Keywords: sialyllactose, milk, oligosaccharides, angiogenesis, VEGF receptor-2
Received: May 31, 2016 Accepted: February 15, 2017 Published: March 14, 2017
The oligosaccharides in human milk have various biological functions. However, the molecular mechanism(s) underlying the anti-angiogenic action of sialylated human milk oligosaccharides (HMOs) are still unclear. Here, we show that siallylactose (SL) found in human milk can inhibit the activation of vascular endothelial growth factor (VEGF)-mediated VEGF receptor-2 (VEGFR-2) by binding to its VEGF binding site (second and third IgG-like domains), thus blocking downstream signal activation. SL also inhibits growth of VEGF-stimulated endothelial cells. In endothelial cells treated with VEGF, SL diminished tube formation, migration, and the arrangement of actin filament. In addition, SL clearly suppressed VEGF-induced neovascularization in an in vivo Matrigel plug assay. Notably, SL prevented the growth of tumor cells, and angiogenesis on tumor tissues in in vivo mice models allotransplanted with Lewis lung carcinoma, melanoma, and colon carcinoma cells. Taken together, we have demonstrated that the sialylated milk oligosaccharide sialyllactose functions as an inhibitor of angiogenesis through suppression of VEGF-mediated VEGFR-2 activation in endothelial cells, Accordingly, it could be a novel candidate for the development of anti-angiogenic drugs without any side effects.
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