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분자활성 촉매반응 연구단
분자활성 촉매반응 연구단
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Fascaplysin exerts anti-cancer effects through the downregulation of survivin and HIF-1α and inhibition of VEGFR2 and TRKA

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Title
Fascaplysin exerts anti-cancer effects through the downregulation of survivin and HIF-1α and inhibition of VEGFR2 and TRKA
Author(s)
Taek-In Oh; Yoon-Mi Lee; Taek-Jin Nam; Young-San Ko; Shinmee Mah; Jinhee Kim; Younghoon Kim; Rallabandi Harikrishna Reddy; Young Jun Kim; Sungwoo Hong; Ji-Hong Lim
Publication Date
2017-10
Journal
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, v.18, no.10, pp.2074 -
Publisher
MDPI AG
Abstract
Fascaplysin has been reported to exert anti-cancer effects by inhibiting cyclin-dependent kinase 4 (CDK4); however, the precise mode of action by which fascaplysin suppresses tumor growth is not clear. Here, we found that fascaplysin has stronger anti-cancer effects than other CDK4 inhibitors, including PD0332991 and LY2835219, on lung cancer cells that are wild-type or null for retinoblastoma (RB), indicating that unknown target molecules might be involved in the inhibition of tumor growth by fascaplysin. Fascaplysin treatment significantly decreased tumor angiogenesis and increased cleaved-caspase-3 in xenografted tumor tissues. In addition, survivin and HIF-1α were downregulated in vitro and in vivo by suppressing 4EBP1-p70S6K1 axis-mediated de novo protein synthesis. Kinase screening assays and drug-protein docking simulation studies demonstrated that fascaplysin strongly inhibited vascular endothelial growth factor receptor 2 (VEGFR2) and tropomyosin-related kinase A (TRKA) via DFG-out non-competitive inhibition. Overall, these results suggest that fascaplysin inhibits TRKA and VEGFR2 and downregulates survivin and HIF-1α, resulting in suppression of tumor growth. Fascaplysin, therefore, represents a potential therapeutic approach for the treatment of multiple types of solid cancer. © 2017 by the authors
URI
http://pr.ibs.re.kr/handle/8788114/3951
DOI
10.3390/ijms18102074
ISSN
1661-6596
Appears in Collections:
Center for Catalytic Hydrocarbon Functionalizations(분자활성 촉매반응 연구단) > Journal Papers (저널논문)
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