Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, Daegu, Republic of Korea.
PLoS One. 2013 Jul 23;8(7):e69380. doi: 10.1371/journal.pone.0069380. Print 2013.
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-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.
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.
蜂毒的主要成分蜂肽（MEL）与关节炎、风湿和各种癌症等多种疾病有关。本研究检测了 MEL 对表皮生长因子（EGF）反应的 CaSki 细胞的抗血管生成作用。
方法/主要发现：MEL 降低了 EGF 诱导的缺氧诱导因子-1α（HIF-1α）蛋白，并显著调节血管生成和肿瘤进展。我们发现，MEL 通过缩短半衰期抑制 HIF-1α 蛋白水平。从机制上讲，MEL 通过抑制 ERK、mTOR 和 p70S6K 的磷酸化来特异性抑制 EGF 诱导的 HIF-1α 表达。它还阻断了 EGF 诱导的 HIF-1α 的 DNA 结合活性和血管内皮生长因子（VEGF）的分泌。此外，染色质免疫沉淀（ChIP）实验表明，MEL 减少了 HIF-1α 与 VEGF 启动子 HRE 区域的结合。MEL 通过抑制 HIF-1α 和 VEGF 表达，在 Matrigel 加样测定中证实了其抗血管生成作用。
MEL 通过抑制 HIF-1α 特异性抑制 EGF 诱导的 VEGF 分泌和新血管形成。这些结果表明，MEL 可能通过抑制 HIF-1α 和 VEGF 表达来抑制人宫颈癌的进展和血管生成。
