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

作者：Jeong Ji Hak; Jeong Yun Jeong; Cho Hyun Ji; Shin Jae Moon; Kang Jeong Han; Park Kwan Kyu; Park Yoon Yub; Chung Il Kyung; Chang Hyeun Wook; Magae Junji; Kang Shin Sung; Chang Young Chae^*

来源：Journal of Cellular Biochemistry, 2012, 113(4): 1302-1313.

DOI：10.1002/jcb.24001

• EGFR
• HIF-1a
• VEGF
• ANGIOGENESIS
• ASCOCHLORIN

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.

• 出版日期2012-4