Melittin Suppresses HIF-1 alpha/VEGF Expression through Inhibition of ERK and mTOR/p70S6K Pathway in Human Cervical Carcinoma Cellsopen access
- Authors
- Shin, Jae-Moon; Jeong, Yun-Jeong; Cho, Hyun-Ji; Park, Kwan-Kyu; Chung, Il-Kyung; Lee, In-Kyu; Kwak, Jong-Young; Chang, Hyeun-Wook; Kim, Cheorl-Ho; Moon, Sung-Kwon; Kim, Wun-Jae; Choi, Yung-Hyun; Chang, Young-Chae
- Issue Date
- Jul-2013
- Publisher
- PUBLIC LIBRARY SCIENCE
- Citation
- PLOS ONE, v.8, no.7
- Journal Title
- PLOS ONE
- Volume
- 8
- Number
- 7
- URI
- https://scholarworks.bwise.kr/cau/handle/2019.sw.cau/14464
- DOI
- 10.1371/journal.pone.0069380
- ISSN
- 1932-6203
- Abstract
- 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.
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