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

作者：Jeong Yun Jeong; Cho Hyun Ji; Magae Junji; Lee In Kyu; Park Keun Gyu^*; Chang Young Chae

来源：Toxicology and Applied Pharmacology, 2013, 273(3): 542-550.

DOI：10.1016/j.taap.2013.09.027

• Ascofuranone
• HIF-1 alpha
• VEGF
• Angiogenesis

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-1 alpha protein accumulation, whereas it did not affect the expression of HIF-1 beta. Furthermore, ascofuranone inhibited the transcriptional activation of vascular endothelial growth factor (VEGF) by reducing protein HIF-1 alpha. Mechanistically, we found that the inhibitory effects of ascofuranone on HIF-1 alpha protein expression are associated with the inhibition of synthesis HIF-1 alpha through an EGF-dependent mechanism. In addition, ascofuranone suppressed EGF-induced phosphotylation 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-1 alpha protein translation through the inhibition of Akt/mTOR/p70S6 kinase signaling pathways and plays a novel role in the antiangiogenic action.

• 出版日期2013-12-15