title: Celastrol inhibits the HIF-1α pathway by inhibition of mTOR/p70S6K/eIF4E and ERK1/2 phosphorylation in human hepatoma cells.
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.
authors.affiliation: 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.
authors.forename: Juan
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Pharmacy, Jilin Province People's Hospital, Changchun, Jilin 130021, P.R. China.
authors.forename: Li Zhuo
authors.initials: LZ
authors.lastname: Han
authors.affiliation: 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.
authors.forename: He
authors.initials: H
authors.lastname: Liang
authors.affiliation: Molecular Cancer Research Center, Yanbian University, Yanji, Jilin 133002, P.R. China.
authors.forename: Chunliu
authors.initials: C
authors.lastname: Mi
authors.affiliation: Molecular Cancer Research Center, Yanbian University, Yanji, Jilin 133002, P.R. China.
authors.forename: Hui
authors.initials: H
authors.lastname: Shi
authors.affiliation: Molecular Cancer Research Center, Yanbian University, Yanji, Jilin 133002, P.R. China.
authors.forename: Jung Joon
authors.initials: JJ
authors.lastname: Lee
authors.affiliation: 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.
authors.forename: Xuejun
authors.initials: X
authors.lastname: Jin
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008114:Liver Neoplasms, Experimental; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D009361:Neoplasm Invasiveness / Q000473:pathology*; D053978:Pentacyclic Triterpenes; D010766:Phosphorylation; D059748:Proteolysis / Q000187:drug effects; D014315:Triterpenes / Q000008:administration & dosage / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D053978:Pentacyclic Triterpenes; D014315:Triterpenes; C050414:celastrol