4-O-methylascochlorin, methylated derivative of ascochlorin, stabilizes HIF-1 alpha via AMPK activation

Title
4-O-methylascochlorin, methylated derivative of ascochlorin, stabilizes HIF-1 alpha via AMPK activation
Author(s)
장현욱Ji-Hak jeong[Ji-Hak jeong]Jeong Han Kang[Jeong Han Kang]Seung-Lark Hwang[Seung-Lark Hwang]Hyun-Ji Cho[Hyun-Ji Cho]Kwan-Kyu Park[Kwan-Kyu Park]Yoon-Yup Park[Yoon-Yup Park]Il-Kyung Chung[Il-Kyung Chung]Cheorl-Ho kim[Cheorl-Ho kim]Kwann-Sik Min[Kwann-Sik Min]Hong-Duck Kim[Hong-Duck Kim]Junji Magae[Junji Magae]Shin-Sung Kang[Shin-Sung Kang]Young-Chae Chang[Young-Chae Chang]
Keywords
INDUCIBLE-FACTOR-I; PROTEIN-KINASE; TRANSCRIPTIONAL ACTIVITY; GENE-EXPRESSION; DOWN-REGULATION; C-MYC; ASCOFURANONE; ANTITUMOR; CELLS; METABOLISM
Issue Date
201103
Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
Citation
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, v.406, no.3, pp.353 - 358
Abstract
Chemopreventive or anticancer agents induce cancer cells to apoptosis through the activation of adenosine AMP-activated protein kinase (AMPK), which plays a major role as energy sensors under ATP-deprived condition or ROS generation. In this study, we compared the effects of ascochlorin (ASC), from the fungus Ascochyta viciae, and its derivatives on AMPK activity. We also examined a regulatory mechanism for hypoxia-inducible factor-1 alpha (HIF-1 alpha) stabilization in response to 4-O-methylascochlorin (MAC). We found that AMPK activation was mainly involved with MAC, but not ASC and 4-O-carboxymethylascochlorin (AS-6), indicating that the substitution of 4-O-methyl group from 4-O-hydroxyl group of ASC is important in the activation of AMPK and the expression of HIF-1 alpha. MAC-stabilized HIF-1 alpha via AMPK activation triggered by lowering the intracellular ATP level, not by ROS generation, increases glucose uptake and the expression of vascular endothelial growth factor (VEGF) and glucose transporter 1 (GLUT-1), major target genes of HIF-1 alpha. moreover, MAC-induced AMPK activity suppressed survival factors, including mTOR and ERK1/2 or translational regulators, including p70S6K and 4E-BP1. Our data suggest that AMPK is a key determinant of MAC-induced HIF-1 alpha expression in response to energy stress, further implying its involvement in MAC-induced apoptosis. (C) 2011 Elsevier Inc. All rights reserved.
URI
http://hdl.handle.net/YU.REPOSITORY/25508http://dx.doi.org/10.1016/j.bbrc.2011.02.043
ISSN
0006-291X
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약학대학 > 약학부 > Articles
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