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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aryl Hydrocarbon Receptor Nuclear Translocator / genetics
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Aryl Hydrocarbon Receptor Nuclear Translocator / metabolism
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Blotting, Western
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Cell Hypoxia / physiology
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Cell Line, Tumor
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Dose-Response Relationship, Drug
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Enzyme Inhibitors / pharmacology
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Gene Expression Regulation, Neoplastic / drug effects
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Guanylate Cyclase / antagonists & inhibitors
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Humans
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Hypoxia-Inducible Factor 1 / genetics
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Hypoxia-Inducible Factor 1 / metabolism*
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
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I-kappa B Kinase / metabolism
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Indazoles / pharmacology*
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Male
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Mitogens / pharmacology
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NF-kappa B / metabolism*
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphorylation / drug effects
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Prostatic Neoplasms / genetics
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Prostatic Neoplasms / metabolism
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Prostatic Neoplasms / pathology
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Protein Kinases / metabolism
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Proto-Oncogene Proteins c-akt / metabolism*
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / drug effects*
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Signal Transduction / physiology
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TOR Serine-Threonine Kinases
Substances
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Enzyme Inhibitors
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Hypoxia-Inducible Factor 1
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Hypoxia-Inducible Factor 1, alpha Subunit
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Indazoles
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Mitogens
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NF-kappa B
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RNA, Messenger
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Aryl Hydrocarbon Receptor Nuclear Translocator
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3-(5'-hydroxymethyl-2'-furyl)-1-benzylindazole
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Protein Kinases
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MTOR protein, human
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Proto-Oncogene Proteins c-akt
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TOR Serine-Threonine Kinases
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I-kappa B Kinase
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Guanylate Cyclase