ascofuranone and Breast-Neoplasms

Hypoxia-inducible factor (HIF)-1 plays an important role in tumor progression, angiogenesis and metastasis. In this study, we investigated the potential molecular mechanisms underlying the anti-angiogenic effect of ascofuranone, an isoprenoid antibiotic from Ascochyta viciae, in epidermal growth factor (EGF)-1 responsive human breast cancer cells. Ascofuranone significantly and selectively suppressed EGF-induced HIF-1α protein accumulation, whereas it did not affect the expression of HIF-1β. Furthermore, ascofuranone inhibited the transcriptional activation of vascular endothelial growth factor (VEGF) by reducing protein HIF-1α. Mechanistically, we found that the inhibitory effects of ascofuranone on HIF-1α protein expression are associated with the inhibition of synthesis HIF-1α through an EGF-dependent mechanism. In addition, ascofuranone suppressed EGF-induced phosphorylation of Akt/mTOR/p70S6 kinase, but the phosphorylation of ERK/JNK/p38 kinase was not affected by ascofuranone. These results suggest that ascofuranone suppresses EGF-induced HIF-1α protein translation through the inhibition of Akt/mTOR/p70S6 kinase signaling pathways and plays a novel role in the anti-angiogenic action.

Topics: Angiogenesis Inhibitors; Animals; Breast Neoplasms; Cell Line, Tumor; Cell Survival; Chromatin Immunoprecipitation; Epidermal Growth Factor; Female; Gene Expression Regulation; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; MCF-7 Cells; Mice; Mice, Inbred C57BL; Neovascularization, Pathologic; Phosphorylation; Proto-Oncogene Proteins c-akt; Ribosomal Protein S6 Kinases, 70-kDa; Sesquiterpenes; Signal Transduction; TOR Serine-Threonine Kinases; Transcriptional Activation; Vascular Endothelial Growth Factor A