Melittin Suppresses HIF-1α/VEGF Expression through Inhibition of ERK and mTOR/p70S6K Pathway in Human Cervical Carcinoma Cells

Objective: Melittin (MEL), a major component of bee venom, has been associated with various diseases including arthritis, rheumatism and various cancers. In this study, the anti-angiogenic effects of MEL in CaSki cells that were responsive to the epidermal growth factor (EGF) were examined. Methodology/Principal Findings: MEL decreased the EGF-induced hypoxia-inducible factor-1 alpha (HIF-1 alpha) protein and significantly regulated angiogenesis and tumor progression. We found that inhibition of the HIF-1 alpha protein level is due to the shortened half-life by MEL. Mechanistically, MEL specifically inhibited the EGF-induced HIF-1 alpha expression by suppressing the phosphorylation of ERK, mTOR and p70S6K. It also blocked the EGF-induced DNA binding activity of HIF-1 alpha and the secretion of the vascular endothelial growth factor (VEGF). Furthermore, the chromatin immunoprecipitation (ChIP) assay revealed that MEL reduced the binding of HIF-1 alpha to the VEGF promoter HRE region. The anti-angiogenesis effects of MEL were confirmed through a matrigel plus assay. Conclusions: MEL specifically suppressed EGF-induced VEGF secretion and new blood vessel formation by inhibiting HIF-1 alpha. These results suggest that MEL may inhibit human cervical cancer progression and angiogenesis by inhibiting HIF-1 alpha and VEGF expression.