YC-1 inhibits HIF-1 expression in prostate cancer cells: Contribution of Akt/NF-κB signaling to HIF-1α accumulation during hypoxia
Journal
Oncogene
Journal Volume
26
Journal Issue
27
Pages
3941-3951
Date Issued
2007
Author(s)
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-1α and HIF-1β accumulation in response to hypoxia or mitogen treatment in PC-3 prostate cancer cells. Neither HIF-1α 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-1α expression at the translational step. We demonstrated that YC-1 also inhibited hypoxia-induced activation of nuclear factor (NF)-κB, a downstream target of Akt. Two modulators of the Akt/NF-κB pathway, caffeic acid phenethyl ester and evodiamine, were observed to decrease HIF-1α expression. Additionally, overexpression of NF-κB partly reversed the ability of wortmannin to inhibit HIF-1α-dependent transcriptional activity, suggesting that NF-κB contributes to Akt-mediated HIF-1α accumulation during hypoxia. Overall, we identify a potential molecular mechanism whereby YC-1 serves to reduce HIF-1 expression. ? 2007 Nature Publishing Group All rights reserved.
Subjects
Akt; HIF-1; NF-κB; Prostate cancer; YC-1
SDGs
Other Subjects
1 benzyl 3 (5 hydroxymethyl 2 furyl)indazole; caffeic acid; evodiamine; hypoxia inducible factor 1; hypoxia inducible factor 1alpha; hypoxia inducible factor 1beta; immunoglobulin enhancer binding protein; initiation factor 4E binding protein; mammalian target of rapamycin; messenger RNA; phosphatidylinositol 3 kinase; protein kinase B; wortmannin; article; controlled study; gene overexpression; human; human cell; hypoxia; male; molecular mechanics; priority journal; prostate cancer; protein expression; RNA translation; signal transduction; transcription regulation; 1-Phosphatidylinositol 3-Kinase; Aryl Hydrocarbon Receptor Nuclear Translocator; Blotting, Western; Cell Hypoxia; Cell Line, Tumor; Dose-Response Relationship, Drug; Enzyme Inhibitors; Gene Expression Regulation, Neoplastic; Guanylate Cyclase; Humans; Hypoxia-Inducible Factor 1; Hypoxia-Inducible Factor 1, alpha Subunit; I-kappa B Kinase; Indazoles; Male; Mitogens; NF-kappa B; Phosphorylation; Prostatic Neoplasms; Protein Kinases; Proto-Oncogene Proteins c-akt; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction
Type
journal article