A quassinoid 6alpha-tigloyloxychaparrinone inhibits hypoxia-inducible factor-1 pathway by inhibition of eukaryotic translation initiation factor 4E phosphorylation.
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 a quassinoid 6alpha-tigloyloxychaparrinone (TCN) as an inhibitor of HIF-1 activation from Ailantus altissima. We here demonstrated the effect of TCN on HIF-1 activation induced by hypoxia or CoCl2. TCN showed the 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. Furthermore, TCN prevented hypoxia-induced expression of HIF-1 target genes for vascular endothelial growth factor (VEGF) and erythropoietin. Further analysis revealed that TCN strongly inhibited HIF-1alpha protein synthesis, without affecting the expression level of HIF-1alpha mRNA or degradation of HIF-1alpha protein. Moreover, the levels of phosphorylation of extracellular signal-regulated kinase-1/2 (ERK1/2), mitogen-activated protein (MAP) kinase-interacting protein kinase-1 (MNK1) and eukaryotic initiation factor 4E (eIF4E) were significantly suppressed by the treatment of TCN, without changing the total levels of these proteins. Our data suggested that TCN may exhibit anticancer activity by inhibiting HIF-1alpha translation through the inhibition of eIF4E phosphorylation pathway and thus provide a novel mechanism for the anticancer activity of quassinoids. TCN could be a new HIF-1-targeted anticancer agent and be effective on mammalian target of rapamycin (mTOR)-targeted cancer therapy, in which mTOR inhibition increases eIF4E phosphorylation.
Jin
Xuejun
X
Center for Molecular Cancer Research, Korea Research Institute of Bioscience and Biotechnology, Daejeon 305-333, Republic of Korea.
Jin
Hong Ri
HR
Lee
Dongho
D
Lee
Jeong-Hyung
JH
Kim
Sang Kyum
SK
Lee
Jung Joon
JJ
D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004797:Enzyme-Linked Immunosorbent Assay; D039561:Eukaryotic Initiation Factor-4E / Q000187:drug effects / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000096:biosynthesis; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors*; D008156:Luciferases / Q000235:genetics; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000187:drug effects; D036702:Quassins / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
D039561:Eukaryotic Initiation Factor-4E; D051793:Hypoxia-Inducible Factor 1; D036702:Quassins; D042461:Vascular Endothelial Growth Factor A; C018679:6 alpha-tigloyloxychaparrinone; D008156:Luciferases; D011494:Protein Kinases; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases