title: 4′,6-dihydroxy-4-methoxyisoaurone inhibits the HIF-1α pathway through inhibition of Akt/mTOR/p70S6K/4E-BP1 phosphorylation.
abstract: 4′,6-Dihydroxy-4-methoxyisoaurone (ISOA) is an isoaurone compound isolated from Trichosanthes kirilowii seeds, which was identified as an inhibitor of tumor growth. However, the mechanism by which ISOA inhibits hypoxia-inducible factor-1 (HIF-1)-mediated tumor growth is not fully understood. We here demonstrated the effect of ISOA on HIF-1 activation. ISOA 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-1a protein dose-dependently, whereas it did not affect the expressions of HIF-1b and topoisomerase-I (Topo-I). Further analysis revealed that the suppression of HIF-1a accumulation by ISOA was closely correlated with strong dephosphorylation of Akt, mammalian target of rapamycin (mTOR), and its effectors ribosomal protein S6 kinase (p70S6K) and eukaryotic initiation factor 4E-binding protein-1 (4E-BP1), a pathway known to regulate HIF-1a expression at the translational level. Furthermore, ISOA prevented hypoxia-induced expression of HIF-1 target genes and suppresses the invasiveness of tumor cells. Taken together, our results suggested that ISOA is an effective inhibitor of HIF-1 through targeting Akt/mTOR/p70S6K/4E-BP1 pathway, thereby, providing new perspectives into the mechanism of its anticancer activity.
authors: Chunliu
authors: C
authors: Mi
authors: Juan
authors: J
authors: Ma
authors: Hui
authors: H
authors: Shi
authors: Jing
authors: J
authors: Li
authors: Fei
authors: F
authors: Wang
authors: Jung Joon
authors: JJ
authors: Lee
authors: Xuejun
authors: X
authors: Jin
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects / Q000235:genetics; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D051793:Hypoxia-Inducible Factor 1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D014176:Protein Biosynthesis / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism*; D012717:Sesquiterpenes / Q000302:isolation & purification / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D029778:Trichosanthes / Q000737:chemistry*
chemical_list: C550949:4',6-dihydroxy-4-methoxyisoaurone; D048868:Adaptor Proteins, Signal Transducing; D000972:Antineoplastic Agents, Phytogenic; D018797:Cell Cycle Proteins; C087000:EIF4EBP1 protein, human; D051793:Hypoxia-Inducible Factor 1; D010750:Phosphoproteins; D012717:Sesquiterpenes; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases