title: 4-O-methylascochlorin, methylated derivative of ascochlorin, stabilizes HIF-1α via AMPK activation.
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-1α (HIF-1α) 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-1α. MAC-stabilized HIF-1α 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-1α. 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-1α expression in response to energy stress, further implying its involvement in MAC-induced apoptosis.
authors.affiliation: Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, Daegu 705-718, Republic of Korea.
authors.forename: Ji-Hak
authors.initials: JH
authors.lastname: Jeong
authors.forename: Jeong Han
authors.initials: JH
authors.lastname: Kang
authors.forename: Seung-Lark
authors.initials: SL
authors.lastname: Hwang
authors.forename: Hyun-Ji
authors.initials: HJ
authors.lastname: Cho
authors.forename: Kwan-Kyu
authors.initials: KK
authors.lastname: Park
authors.forename: Yoon-Yup
authors.initials: YY
authors.lastname: Park
authors.forename: Il-Kyung
authors.initials: IK
authors.lastname: Chung
authors.forename: Hyeun-Wook
authors.initials: HW
authors.lastname: Chang
authors.forename: Cheorl-Ho
authors.initials: CH
authors.lastname: Kim
authors.forename: Kwan-Sik
authors.initials: KS
authors.lastname: Min
authors.forename: Hong-Duck
authors.initials: HD
authors.lastname: Kim
authors.forename: Junji
authors.initials: J
authors.lastname: Magae
authors.forename: Shin-Sung
authors.initials: SS
authors.lastname: Kang
authors.forename: Young-Chae
authors.initials: YC
authors.lastname: Chang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000475:Alkenes / Q000737:chemistry / Q000494:pharmacology*; D017209:Apoptosis; D045744:Cell Line, Tumor; D055785:Gene Knockdown Techniques; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D008745:Methylation; D010636:Phenols / Q000737:chemistry / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects; D055550:Protein Stability; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000037:antagonists & inhibitors; D038762:Ribosomal Protein S6 Kinases, 70-kDa / Q000378:metabolism; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013729:Terpenes / Q000494:pharmacology*
chemical_list: D000475:Alkenes; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D010636:Phenols; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D013729:Terpenes; C031515:4-O-methylascochlorin; D000255:Adenosine Triphosphate; C546842:MTOR protein, human; D038762:Ribosomal Protein S6 Kinases, 70-kDa; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; C415745:ascochlorin