PMID- 24859482
OWN - NLM
STAT- MEDLINE
DCOM- 20150114
LR  - 20211203
IS  - 1791-2431 (Electronic)
IS  - 1021-335X (Linking)
VI  - 32
IP  - 1
DP  - 2014 Jul
TI  - Celastrol inhibits the HIF-1alpha pathway by inhibition of mTOR/p70S6K/eIF4E and 
      ERK1/2 phosphorylation in human hepatoma cells.
PG  - 235-42
LID - 10.3892/or.2014.3211 [doi]
AB  - 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-1alpha 
      protein dose-dependently, whereas it did not affect the expressions of HIF-1beta 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-1alpha protein synthesis, without affecting the expression level of HIF-1alpha mRNA 
      or degradation of HIF-1alpha protein. Markedly, we found that suppression of HIF-1alpha 
      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-1alpha expression at 
      the translational level. In vivo studies further confirmed the inhibitory effect 
      of celastrol on the expression of HIF-1alpha 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.
FAU - Ma, Juan
AU  - Ma J
AD  - 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.
FAU - Han, Li Zhuo
AU  - Han LZ
AD  - Department of Pharmacy, Jilin Province People's Hospital, Changchun, Jilin 
      130021, P.R. China.
FAU - Liang, He
AU  - Liang H
AD  - 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.
FAU - Mi, Chunliu
AU  - Mi C
AD  - Molecular Cancer Research Center, Yanbian University, Yanji, Jilin 133002, P.R. 
      China.
FAU - Shi, Hui
AU  - Shi H
AD  - Molecular Cancer Research Center, Yanbian University, Yanji, Jilin 133002, P.R. 
      China.
FAU - Lee, Jung Joon
AU  - Lee JJ
AD  - Molecular Cancer Research Center, Yanbian University, Yanji, Jilin 133002, P.R. 
      China.
FAU - Jin, Xuejun
AU  - Jin X
AD  - 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.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20140523
PL  - Greece
TA  - Oncol Rep
JT  - Oncology reports
JID - 9422756
RN  - 0 (Hypoxia-Inducible Factor 1, alpha Subunit)
RN  - 0 (Pentacyclic Triterpenes)
RN  - 0 (Triterpenes)
RN  - L8GG98663L (celastrol)
SB  - IM
MH  - Animals
MH  - Carcinoma, Hepatocellular/*drug therapy/pathology
MH  - Cell Line, Tumor
MH  - Dose-Response Relationship, Drug
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - HeLa Cells
MH  - Humans
MH  - Hypoxia-Inducible Factor 1, alpha Subunit/*antagonists & inhibitors/metabolism
MH  - Liver Neoplasms/*drug therapy/pathology
MH  - Liver Neoplasms, Experimental
MH  - MAP Kinase Signaling System/drug effects
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Neoplasm Invasiveness/*pathology
MH  - Pentacyclic Triterpenes
MH  - Phosphorylation
MH  - Proteolysis/drug effects
MH  - Triterpenes/administration & dosage/*pharmacology
MH  - Xenograft Model Antitumor Assays
EDAT- 2014/05/27 06:00
MHDA- 2015/01/15 06:00
CRDT- 2014/05/27 06:00
PHST- 2014/03/11 00:00 [received]
PHST- 2014/05/06 00:00 [accepted]
PHST- 2014/05/27 06:00 [entrez]
PHST- 2014/05/27 06:00 [pubmed]
PHST- 2015/01/15 06:00 [medline]
AID - 10.3892/or.2014.3211 [doi]
PST - ppublish
SO  - Oncol Rep. 2014 Jul;32(1):235-42. doi: 10.3892/or.2014.3211. Epub 2014 May 23.