Dehydrocostuslactone suppresses angiogenesis in vitro and in vivo through inhibition of AKT/GSK-3β and mtor signaling pathways

Chih Ya Wang, An Chi Tsai, Chieh Yu Peng, Ya Ling Chang, Kuo Hsiung Lee, Che Ming Teng, Shiow Lin Pan

Research output: Contribution to journalArticle

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Abstract

The traditional Chinese medicine component dehydrocostuslactone (DHC) isolated from Saussurea costus (Falc.) Lipschitz, has been shown to have anti-cancer activity. Angiogenesis is an essential process in the growth and progression of cancer. In this study, we demonstrated, for the first time, the anti-angiogenic mechanism of action of DHC to be via the induction of cell cycle progression at the G0/G1 phase due to abrogation of the Akt/glycogen synthase kinase-3β (GSK-3β)/cyclin D1 and mTOR signaling pathway. First, we demonstrated that DHC has an anti-angiogenic effect in the matrigel-plug nude mice model and an inhibitory effect on human umbilical vein endothelial cell (HUVEC) proliferation and capillary-like tube formation in vitro. DHC caused G0/G1 cell cycle arrest, which was associated with the down-regulation of cyclin D1 expression, leading to the suppression of retinoblastoma protein phosphorylation and subsequent inhibition of cyclin A and cdk2 expression. With respect to the molecular mechanisms underlying the DHC-induced cyclin D1 down-regulation, this study demonstrated that DHC significantly inhibits Akt expression, resulting in the suppression of GSK-3β phosphorylation and mTOR expression. These effects are capable of regulating cyclin D1 degradation, but they were significantly reversed by constitutively active myristoylated (myr)-Akt. Furthermore, the abrogation of tube formation induced by DHC was also reversed by overexpression of Akt. And the co-treatment with LiCl and DHC significantly reversed the growth inhibition induced by DHC. Taken together, our study has identified Akt/GSK-3β and mTOR as important targets of DHC and has thus highlighted its potential application in angiogenesis-related diseases, such as cancer.

Original languageEnglish
Article numbere31195
JournalPLoS One
Volume7
Issue number2
DOIs
Publication statusPublished - Feb 16 2012
Externally publishedYes

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Glycogen Synthase Kinase 3
cyclins
angiogenesis
Cyclin D1
neoplasms
Saussurea costus
Phosphorylation
cyclin-dependent kinase
protein phosphorylation
interphase
growth retardation
cell cycle
mechanism of action
cell proliferation
phosphorylation
medicine
Saussurea
Down-Regulation
animal models
Cells

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Dehydrocostuslactone suppresses angiogenesis in vitro and in vivo through inhibition of AKT/GSK-3β and mtor signaling pathways. / Wang, Chih Ya; Tsai, An Chi; Peng, Chieh Yu; Chang, Ya Ling; Lee, Kuo Hsiung; Teng, Che Ming; Pan, Shiow Lin.

In: PLoS One, Vol. 7, No. 2, e31195, 16.02.2012.

Research output: Contribution to journalArticle

Wang, Chih Ya ; Tsai, An Chi ; Peng, Chieh Yu ; Chang, Ya Ling ; Lee, Kuo Hsiung ; Teng, Che Ming ; Pan, Shiow Lin. / Dehydrocostuslactone suppresses angiogenesis in vitro and in vivo through inhibition of AKT/GSK-3β and mtor signaling pathways. In: PLoS One. 2012 ; Vol. 7, No. 2.
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