title: Suppression of c-Myc induces apoptosis via an AMPK/mTOR-dependent pathway by 4-O-methyl-ascochlorin in leukemia cells.
abstract: 4-O-Methyl-ascochlorin (MAC) is a methylated derivative of the prenyl-phenol antibiotic ascochlorin, which was isolated from an incomplete fungus, Ascochyta viciae. Although the effects of MAC on apoptosis have been reported, the underlying mechanisms remain unknown. Here, we show that MAC promoted apoptotic cell death and downregulated c-Myc expression in K562 human leukemia cells. The effect of MAC on apoptosis was similar to that of 10058-F4 (a c-Myc inhibitor) or c-Myc siRNA, suggesting that the downregulation of c-Myc expression plays a role in the apoptotic effect of MAC. Further investigation showed that MAC downregulated c-Myc by inhibiting protein synthesis. MAC promoted the phosphorylation of AMP-activated protein kinase (AMPK) and inhibited the phosphorylation of mammalian target of rapamycin (mTOR) and its target proteins, including p70S6 K and 4E-BP-1. Treatment of cells with AICAR (an AMPK activator), rapamycin (an mTOR inhibitor), or mTOR siRNA downregulated c-Myc expression and induced apoptosis to a similar extent to that of MAC. These results suggest that the effect of MAC on apoptosis induction in human leukemia cells is mediated by the suppression of c-Myc protein synthesis via an AMPK/mTOR-dependent mechanism.
authors.affiliation: Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, 3056-6, Daemyung-4-Dong, Nam-gu, Daegu, 705-718, Republic of Korea.|School of Life Sciences, College of Natural Sciences, KNU Creative BioResearch Group (BK21 Plus Program), Kyungpook National University, Sangyeok 3-dong, Buk-gu, Daegu, 702-701, Republic of Korea.
authors.forename: Jae-Moon
authors.initials: JM
authors.lastname: Shin
authors.affiliation: Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, 3056-6, Daemyung-4-Dong, Nam-gu, Daegu, 705-718, Republic of Korea.
authors.forename: Yun-Jeong
authors.initials: YJ
authors.lastname: Jeong
authors.affiliation: Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, 3056-6, Daemyung-4-Dong, Nam-gu, Daegu, 705-718, Republic of Korea.|Department of Neural Development and Disease, Korea Brain Research Institute (KBRI), Daegu, 701-300, Republic of Korea.
authors.forename: Hyun-Ji
authors.initials: HJ
authors.lastname: Cho
authors.affiliation: Magae Bioscience Institute, 49-4 Fujimidai, Tsukuba, 300-1263, Japan.
authors.forename: Junji
authors.initials: J
authors.lastname: Magae
authors.affiliation: School of Life Sciences, College of Natural Sciences, KNU Creative BioResearch Group (BK21 Plus Program), Kyungpook National University, Sangyeok 3-dong, Buk-gu, Daegu, 702-701, Republic of Korea. ysbae@knu.ac.kr.
authors.forename: Young-Seuk
authors.initials: YS
authors.lastname: Bae
authors.affiliation: Research Institute of Biomedical Engineering and Department of Medicine, Catholic University of Daegu School of Medicine, 3056-6, Daemyung-4-Dong, Nam-gu, Daegu, 705-718, Republic of Korea. ycchang@cu.ac.kr.
authors.forename: Young-Chae
authors.initials: YC
authors.lastname: Chang
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D002460:Cell Line; D045744:Cell Line, Tumor; D059585:G1 Phase Cell Cycle Checkpoints; D006801:Humans; D020014:K562 Cells; D014176:Protein Biosynthesis / Q000187:drug effects; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013729:Terpenes / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D016271:Proto-Oncogene Proteins c-myc; D013729:Terpenes; C031515:4-O-methylascochlorin; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases
keywords: 4-O-Methyl-ascochlorin (MAC); AMPK; Apoptosis; c-Myc; mTOR