Ascochlorin inhibits growth factor-induced HIF-1a activation and tumor-angiogenesis through the suppression of EGFR/ERK/p70S6K signaling pathway in human cervical carcinoma cells

Title
Ascochlorin inhibits growth factor-induced HIF-1a activation and tumor-angiogenesis through the suppression of EGFR/ERK/p70S6K signaling pathway in human cervical carcinoma cells
Author(s)
장현욱정지학[정지학]정윤정[정윤정]조현지[조현지]신재문[신재문]강정한[강정한]박관규[박관규]박윤엽[박윤엽]정일경[정일경]Junji Magae[Junji Magae]강신성[강신성]장영채[장영채]
Keywords
INDUCIBLE FACTOR 1-ALPHA; PROLYL HYDROXYLATION; DOWN-REGULATION; FACTOR-I; C-MYC; HYPOXIA; HIF-1-ALPHA; ASCOFURANONE; EXPRESSION; FAMILY
Issue Date
201204
Publisher
WILEY-BLACKWELL
Citation
JOURNAL OF CELLULAR BIOCHEMISTRY, v.113, no.4, pp.1302 - 1313
Abstract
Ascochlorin, a non-toxic prenylphenol compound derived from the fungus Ascochyta viciae, has been shown recently to have anti-cancer effects on various human cancer cells. However, the precise molecular mechanism of this anti-cancer activity remains to be elucidated. Here, we investigated the effects of ascochlorin on hypoxia-inducible factor-1a (HIF-1a) and vascular endothelial growth factor (VEGF) expression in human epidermoid cervical carcinoma CaSki cells. Ascochlorin inhibited epidermal growth factor (EGF)-induced HIF-1a and VEGF expression through multiple potential mechanisms. First, ascochlorin selectively inhibited HIF-1a expression in response to EGF stimulation, but not in response to hypoxia (1% O2) or treatment with a transition metal (CoCl2). Second, ascochlorin inhibited EGF-induced ERK-1/2 activation but not AKT activation, both of which play essential roles in EGF-induced HIF-1a protein synthesis. Targeted inhibition of epidermal growth factor receptor (EGFR) expression using an EGFR-specific small interfering RNA (siRNA) diminished HIF-1a expression, which suggested that ascochlorin inhibits HIF-1a expression through suppression of EGFR activation. Finally, we showed that ascochlorin functionally abrogates in vivo tumor angiogenesis induced by EGF in a Matrigel plug assay. Our data suggest that ascochlorin inhibits EGF-mediated induction of HIF-1a expression in CaSki cells, providing a potentially new avenue of development of anti-cancer drugs that target tumor angiogenesis. J. Cell. Biochem. 113: 13021313, 2012. (c) 2011 Wiley Periodicals, Inc.
URI
http://hdl.handle.net/YU.REPOSITORY/28588http://dx.doi.org/10.1002/jcb.24001
ISSN
0730-2312
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약학대학 > 약학부 > Articles
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