Celastrol inhibits the HIF-1α pathway by inhibition of mTOR/p70S6K/eIF4E and ERK1/2 phosphorylation in human hepatoma cells

Ma,Juan; Han,Li  Zhuo; Liang,He; Mi,Chunliu; Shi,Hui; Lee,Jung  Joon; Jin,Xuejun

doi:10.3892/or.2014.3211

Celastrol inhibits the HIF-1α pathway by inhibition of mTOR/p70S6K/eIF4E and ERK1/2 phosphorylation in human hepatoma cells

Authors:
- Juan Ma
- Li Zhuo Han
- He Liang
- Chunliu Mi
- Hui Shi
- Jung Joon Lee
- Xuejun Jin
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Affiliations: Key Laboratory of Natural Resources of Changbai Mountain and Functional Molecules, Ministry of Education, College of Pharmacy, Yanbian University, Yanji, Jilin 133002, P.R. China, Department of Pharmacy, Jilin Province People's Hospital, Changchun, Jilin 130021, P.R. China, Molecular Cancer Research Center, Yanbian University, Yanji, Jilin 133002, P.R. China
Published online on: May 23, 2014 https://doi.org/10.3892/or.2014.3211
Pages: 235-242

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Abstract

Hypoxia-inducible factor-1 (HIF-1) is the central mediator of cellular responses to low oxygen and vital to many aspects of cancer biology. In a search for HIF-1 inhibitors, we identified celastrol as an inhibitor of HIF-1 activation from Tripterygium wilfordii. In the present study, we demonstrated the effect of celastrol on HIF-1 activation. Celastrol showed a potent inhibitory activity against HIF-1 activation induced by hypoxia in various human cancer cell lines. This compound markedly decreased the hypoxia-induced accumulation of HIF-1α protein dose-dependently, whereas it did not affect the expressions of HIF-1β and topoisomerase-I (topo‑I). Furthermore, celastrol prevented hypoxia-induced expression of HIF-1 target genes for vascular endothelial growth factor (VEGF) and erythropoietin (EPO). Further analysis revealed that celastrol inhibited HIF-1α protein synthesis, without affecting the expression level of HIF-1α mRNA or degradation of HIF-1α protein. Markedly, we found that suppression of HIF-1α accumulation by celastrol correlated with strong dephosphorylation of mammalian target of rapamycin (mTOR) and its effectors, ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E (eIF4E) and extracellular signal-regulated kinase (ERK), pathways known to regulate HIF-1α expression at the translational level. In vivo studies further confirmed the inhibitory effect of celastrol on the expression of HIF-1α proteins, leading to a decreased growth of Hep3B cells in a xenograft tumor model. Our data suggested that celastrol is an effective inhibitor of HIF-1 and provide new perspectives into the mechanism of its anticancer activity.

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