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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.RESULTS
MEL decreased the EGF-induced hypoxia-inducible factor-1α (HIF-1α) protein and significantly regulated angiogenesis and tumor progression. We found that inhibition of the HIF-1α protein level is due to the shortened half-life by MEL. Mechanistically, MEL specifically inhibited the EGF-induced HIF-1α expression by suppressing the phosphorylation of ERK, mTOR and p70S6K. It also blocked the EGF-induced DNA binding activity of HIF-1α and the secretion of the vascular endothelial growth factor (VEGF). Furthermore, the chromatin immunoprecipitation (ChIP) assay revealed that MEL reduced the binding of HIF-1α 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-1α. These results suggest that MEL may inhibit human cervical cancer progression and angiogenesis by inhibiting HIF-1α and VEGF expression.
ERK ⊣ MEL: " Mechanistically, MEL specifically inhibited the EGF induced HIF-1a expression by suppressing the phosphorylation of ERK , mTOR and p70S6K "
mTOR ⊣ MEL: " Mechanistically, MEL specifically inhibited the EGF induced HIF-1a expression by suppressing the phosphorylation of ERK, mTOR and p70S6K "
p70S6K ⊣ MEL: " Mechanistically, MEL specifically inhibited the EGF induced HIF-1a expression by suppressing the phosphorylation of ERK, mTOR and p70S6K "
HIF-1a → EGF: " Mechanistically, MEL specifically inhibited the EGF induced HIF-1a expression by suppressing the phosphorylation of ERK, mTOR and p70S6K "
HIF-1a → ERK: " Mechanistically, MEL specifically inhibited the EGF induced HIF-1a expression by suppressing the phosphorylation of ERK , mTOR and p70S6K "
HIF-1a → mTOR: " Mechanistically, MEL specifically inhibited the EGF induced HIF-1a expression by suppressing the phosphorylation of ERK, mTOR and p70S6K "
HIF-1a → p70S6K: " Mechanistically, MEL specifically inhibited the EGF induced HIF-1a expression by suppressing the phosphorylation of ERK, mTOR and p70S6K "
vascular endothelial growth factor → EGF: " It also blocked the EGF induced DNA binding activity of HIF-1a and the secretion of the vascular endothelial growth factor ( VEGF ) "
HIF-1a → EGF: " It also blocked the EGF induced DNA binding activity of HIF-1a and the secretion of the vascular endothelial growth factor ( VEGF ) "
HIF-1a ⊣ MEL: " Furthermore, the chromatin immunoprecipitation ( ChIP ) assay revealed that MEL reduced the binding of HIF-1a to the VEGF promoter HRE region "
VEGF ⊣ MEL: " MEL specifically suppressed EGF induced VEGF secretion and new blood vessel formation by inhibiting HIF-1a "
VEGF → EGF: " MEL specifically suppressed EGF induced VEGF secretion and new blood vessel formation by inhibiting HIF-1a "
VEGF ⊣ MEL: " These results suggest that MEL may inhibit human cervical cancer progression and angiogenesis by inhibiting HIF-1a and VEGF expression "
HIF-1a ⊣ MEL: " These results suggest that MEL may inhibit human cervical cancer progression and angiogenesis by inhibiting HIF-1a and VEGF expression "