Ascofuranone suppresses EGF-induced HIF-1α protein synthesis by inhibition of the Akt/mTOR/p70S6K pathway in MDA-MB-231 breast cancer cells.

Abstract

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.

• Authors: Yun-Jeong Jeong, Hyun-Ji Cho, Junji Magae, In-Kyu Lee, Keun-Gyu Park, Young-Chae Chang
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 273 Issue 3 Pg. 542-50 (Dec 15 2013) ISSN: 1096-0333 [Electronic] United States
• PMID: 24096035 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013.

Chemical References

• Angiogenesis Inhibitors
• HIF1A protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• Sesquiterpenes
• VEGFA protein, human
• Vascular Endothelial Growth Factor A
• Epidermal Growth Factor
• MTOR protein, human
• Proto-Oncogene Proteins c-akt
• Ribosomal Protein S6 Kinases, 70-kDa
• TOR Serine-Threonine Kinases
• ascofuranone

Topics

• Angiogenesis Inhibitors (pharmacology)
• Animals
• Breast Neoplasms (genetics)
• Cell Line, Tumor
• Cell Survival
• Chromatin Immunoprecipitation
• Epidermal Growth Factor (pharmacology)
• Female
• Gene Expression Regulation
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (antagonists & inhibitors, biosynthesis)
• MCF-7 Cells
• Mice
• Mice, Inbred C57BL
• Neovascularization, Pathologic (drug therapy)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• Ribosomal Protein S6 Kinases, 70-kDa (metabolism)
• Sesquiterpenes (pharmacology)
• Signal Transduction (drug effects)
• TOR Serine-Threonine Kinases (metabolism)
• Transcriptional Activation
• Vascular Endothelial Growth Factor A (antagonists & inhibitors, metabolism)