Aminoflavone, a Ligand of the Aryl Hydrocarbon Receptor, Inhibits HIF-1α Expression in an AhR-Independent Fashion
| Autor: | Marina Ziche, Badarch Uranchimeg, Maura Puppo, Erika Terzuoli, Annamaria Rapisarda, Liang Cao, Angelika M. Burger, Giovanni Melillo |
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| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
Transcription Genetic Mice Nude Breast Neoplasms Ligands Article Mice Downregulation and upregulation Cell Line Tumor Gene expression Basic Helix-Loop-Helix Transcription Factors Animals Humans RNA Messenger RNA Small Interfering Receptor Transcription factor Flavonoids biology Transfection Hypoxia-Inducible Factor 1 alpha Subunit Aryl hydrocarbon receptor Xenograft Model Antitumor Assays Molecular biology Cell biology Receptors Aryl Hydrocarbon Oncology Cell culture biology.protein Female Signal transduction DNA Damage |
| Zdroj: | Cancer Research. 70:6837-6848 |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-10-1075 |
| Popis: | Aminoflavone (AF), the active component of a novel anticancer agent (AFP464) in phase I clinical trials, is a ligand of the aryl hydrocarbon receptor (AhR). AhR dimerizes with HIF-1β/AhR, which is shared with HIF-1α, a transcription factor critical for the response of cells to oxygen deprivation. To address whether pharmacologic activation of the AhR pathway might be a potential mechanism for inhibition of HIF-1, we tested the effects of AF on HIF-1 expression. AF inhibited HIF-1α transcriptional activity and protein accumulation in MCF-7 cells. However, inhibition of HIF-1α by AF was independent from a functional AhR pathway. Indeed, AF inhibited HIF-1α expression in AhR100 cells, in which the AhR pathway is functionally impaired, yet did not induce cytotoxicity, providing evidence that these effects are mediated by distinct signaling pathways. Moreover, AF was inactive in MDA-MB-231 cells, yet inhibited HIF-1α in MDA-MB-231 cells transfected with the SULT1A1 gene. AF inhibited HIF-1α mRNA expression by ∼50%. Notably, actinomycin-D completely abrogated the ability of AF to downregulate HIF-1α mRNA, indicating that active transcription was required for the inhibition of HIF-1α expression. Finally, AF inhibited HIF-1α protein accumulation and the expression of HIF-1 target genes in MCF-7 xenografts. These results show that AF inhibits HIF-1α in an AhR-independent fashion, and they unveil additional activities of AF that may be relevant for its further clinical development. Cancer Res; 70(17); 6837–48. ©2010 AACR. |
| Databáze: | OpenAIRE |
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