title: YC-1 inhibits HIF-1 expression in prostate cancer cells: contribution of Akt/NF-kappaB signaling to HIF-1alpha accumulation during hypoxia.
abstract: Hypoxia-inducible factor 1 (HIF-1), a transcription factor that is critical for tumor adaptation to microenvironmental stimuli, represents an attractive chemotherapeutic target. YC-1 is a novel antitumor agent that inhibits HIF-1 through previously unexplained mechanisms. In the present study, YC-1 was found to prevent HIF-1alpha and HIF-1beta accumulation in response to hypoxia or mitogen treatment in PC-3 prostate cancer cells. Neither HIF-1alpha protein half-life nor mRNA level was affected by YC-1. However, YC-1 was found to suppress the PI3K/Akt/mTOR/4E-BP pathway, which serves to regulate HIF-1alpha expression at the translational step. We demonstrated that YC-1 also inhibited hypoxia-induced activation of nuclear factor (NF)-kappaB, a downstream target of Akt. Two modulators of the Akt/NF-kappaB pathway, caffeic acid phenethyl ester and evodiamine, were observed to decrease HIF-1alpha expression. Additionally, overexpression of NF-kappaB partly reversed the ability of wortmannin to inhibit HIF-1alpha-dependent transcriptional activity, suggesting that NF-kappaB contributes to Akt-mediated HIF-1alpha accumulation during hypoxia. Overall, we identify a potential molecular mechanism whereby YC-1 serves to reduce HIF-1 expression.
authors.affiliation: Pharmacological Institute, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: H-L
authors.initials: HL
authors.lastname: Sun
authors.forename: Y-N
authors.initials: YN
authors.lastname: Liu
authors.forename: Y-T
authors.initials: YT
authors.lastname: Huang
authors.forename: S-L
authors.initials: SL
authors.lastname: Pan
authors.forename: D-Y
authors.initials: DY
authors.lastname: Huang
authors.forename: J-H
authors.initials: JH
authors.lastname: Guh
authors.forename: F-Y
authors.initials: FY
authors.lastname: Lee
authors.forename: S-C
authors.initials: SC
authors.lastname: Kuo
authors.forename: C-M
authors.initials: CM
authors.lastname: Teng
mesh_terms: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D015687:Cell Hypoxia / Q000502:physiology; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000235:genetics / Q000378:metabolism*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D051550:I-kappa B Kinase / Q000378:metabolism; D007191:Indazoles / Q000494:pharmacology*; D008297:Male; D008934:Mitogens / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011494:Protein Kinases / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D058570:TOR Serine-Threonine Kinases
chemical_list: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D004791:Enzyme Inhibitors; D006162:Guanylate Cyclase; D051793:Hypoxia-Inducible Factor 1; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D051550:I-kappa B Kinase; D007191:Indazoles; D008934:Mitogens; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D012333:RNA, Messenger; D058570:TOR Serine-Threonine Kinases; C090937:3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole; C546842:MTOR protein, human