YC-1 inhibits HIF-1 expression in prostate cancer cells: contribution of Akt/NF-kappaB signaling to HIF-1alpha accumulation during hypoxia
| Autor: | Chen-Hsin Teng, Kuo Sc, Liu Yn, Pan Sl, Jih H. Guh, Yun-Ju Huang, Lee Fy, Huang Dy, Sun Hl |
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| Rok vydání: | 2007 |
| Předmět: |
Male
Cancer Research medicine.medical_specialty Indazoles Blotting Western Biology Wortmannin chemistry.chemical_compound Phosphatidylinositol 3-Kinases Internal medicine Cell Line Tumor Genetics medicine Humans RNA Messenger Enzyme Inhibitors Phosphorylation Caffeic acid phenethyl ester Molecular Biology Protein kinase B Transcription factor PI3K/AKT/mTOR pathway Regulation of gene expression Dose-Response Relationship Drug Reverse Transcriptase Polymerase Chain Reaction TOR Serine-Threonine Kinases Aryl Hydrocarbon Receptor Nuclear Translocator NF-kappa B Prostatic Neoplasms NF-κB Hypoxia-Inducible Factor 1 alpha Subunit Cell Hypoxia I-kappa B Kinase Gene Expression Regulation Neoplastic Endocrinology chemistry Guanylate Cyclase Cancer research Hypoxia-Inducible Factor 1 Signal transduction Mitogens Protein Kinases Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Oncogene. 26(27) |
| ISSN: | 0950-9232 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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