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Int J Mol Sci. 2017 Sep 29;18(10). pii: E2074. doi: 10.3390/ijms18102074.

Fascaplysin Exerts Anti-Cancer Effects through the Downregulation of Survivin and HIF-1α and Inhibition of VEGFR2 and TRKA.

Oh TI1, Lee YM2,3, Nam TJ4, Ko YS5, Mah S6,7, Kim J8,9, Kim Y10, Reddy RH11, Kim YJ12,13, Hong S14,15, Lim JH16,17.

Author information

1
Department of Biomedical Chemistry, College of Biomedical & Health Science, Konkuk University, Chungju 27478, Chungbuk, Korea. dk1050@kku.ac.kr.
2
Department of Food Bioscience, College of Biomedical & Health Science, Konkuk University, Chungju 27478, Chungbuk, Korea. yoonmilee@kku.ac.kr.
3
Nanotechnology Research Center, Konkuk University, Chungju 27478, Chungbuk, Korea. yoonmilee@kku.ac.kr.
4
Department of Biomedical Chemistry, College of Biomedical & Health Science, Konkuk University, Chungju 27478, Chungbuk, Korea. tj1994s@naver.com.
5
Department of Anatomy, Seoul National University College of Medicine, Seoul 03080, Korea. rhdudtks@snu.ac.kr.
6
Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Korea. msm115@kaist.ac.kr.
7
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea. msm115@kaist.ac.kr.
8
Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Korea. chem88@kaist.ac.kr.
9
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea. chem88@kaist.ac.kr.
10
Department of Pathology, Seoul National University College of Medicine, Seoul 03080, Korea. manofme@naver.com.
11
Department of Biomedical Chemistry, College of Biomedical & Health Science, Konkuk University, Chungju 27478, Chungbuk, Korea. harikrishnareddy.6@gmail.com.
12
Department of Biomedical Chemistry, College of Biomedical & Health Science, Konkuk University, Chungju 27478, Chungbuk, Korea. ykim@kku.ac.kr.
13
Nanotechnology Research Center, Konkuk University, Chungju 27478, Chungbuk, Korea. ykim@kku.ac.kr.
14
Center for Catalytic Hydrocarbon Functionalizations, Institute for Basic Science (IBS), Daejeon 34141, Korea. hongorg@kaist.ac.kr.
15
Department of Chemistry, Korea Advanced Institute of Science and Technology (KAIST), Daejeon 34141, Korea. hongorg@kaist.ac.kr.
16
Department of Biomedical Chemistry, College of Biomedical & Health Science, Konkuk University, Chungju 27478, Chungbuk, Korea. jhlim@kku.ac.kr.
17
Nanotechnology Research Center, Konkuk University, Chungju 27478, Chungbuk, Korea. jhlim@kku.ac.kr.

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.

KEYWORDS:

TRAIL; TRKA; VEGFR2; fascaplysin; survivin

PMID:
28961193
PMCID:
PMC5666756
DOI:
10.3390/ijms18102074
[Indexed for MEDLINE]
Free PMC Article

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