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Life Science : Ascochlorin activates p53 in a manner distinct from DNA damaging agents
( Ji Hak Jeong ),( Hiroo Nakajima ),( Junji Magae ),( Chiharu Furukawa ),( Keiko Taki ),( Kensuke Otsuka ),( Masanori Tomita ),( In Seon Lee ),( Cheorl Ho Kim ),( Hyeun Wook Chang ),( Kwan Sik Min ),( 영남대학교 약품개발연구소 2009 영남대학교 약품개발연구소 연구업적집 Vol.19 No.-
Ascochlorin activates p53 in a manner distinct from DNA damaging agents
Jeong, Ji-Hak,Nakajima, Hiroo,Magae, Junji,Furukawa, Chiharu,Taki, Keiko,Otsuka, Kensuke,Tomita, Masanori,Lee, In-Seon,Kim, Cheorl-Ho,Chang, Hyeun-Wook,Min, Kwan-Sik,Park, Kwang-Kyun,Park, Kwan-Kyu,Ch Wiley Subscription Services, Inc., A Wiley Company 2009 International journal of cancer: Journal internati Vol.124 No.12
<P>Ascochlorin, a prenylphenol antitumor antibiotic, profoundly increases the expression of endogenous p53 by increasing protein stability in the human osteosarcoma cells and human colon cancer cells. Ascochlorin also increases DNA binding activity to the p53 consensus sequence in nuclear extract and enhances transcription of p53 downstream targets. Ascochlorin specifically induces p53 phosphorylation at ser 392 without affecting ser 15 or 20, whereas DNA damaging agents typically phosphorylate these serines. Moreover, ascochlorin does not induce phosphorylation of ATM and CHK1, an established substrate of ATR that is activated by genotoxins, nor does it increase DNA strand break, as confirmed by comet assay. The structure-activity relationship suggests that p53 activation by ascochlorin is related to inhibition of mitochondrial respiration, which is further supported by the observation that respiratory inhibitors activate p53 in a manner similar to ascochlorin. These results suggest that ascochlorin, through the inhibition of mitochondrial respiration, activates p53 through a mechanism distinct from genotoxins. © 2009 UICC</P>
Shin, J. M.,Jeong, Y. J.,Cho, H. J.,Magae, J.,Bae, Y. S.,Chang, Y. C. Springer Science + Business Media 2016 Apoptosis Vol.21 No.5
<P>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.</P>
MAC inhibits c-Myc and induces autophagy by downregulation of CIP2A in leukemia cells
황순경,Yun-Jeong Jeong,Jae-Moon Shin,Junji Magae,CHEORL-HO KIM,장영채 대한독성 유전단백체 학회 2018 Molecular & cellular toxicology Vol.14 No.4
Backgrounds: 4-O-methyl-ascochlorin (MAC) is a methylated derivative of the prenyl-phenol antibiotic ascochlorin, which was isolated from the incomplete fungus Ascochyta viciae. We have recently shown that MAC promotes apoptotic cell death by inhibiting c-Myc expression in K562 leukemia cells, but the effects of MAC on autophagy are still unknown. Methods: Treatment of MAC significantly increased LC3 expression and autophagic vesicle formation by western blot and acridine orange staining. Also, we examined the possible mechanisms underlying MAC induced autophagy. Results: We found that MAC suppressed c-Myc expression by inhibiting CIP2A (regulator of c-Myc) protein synthesis. This result suggests that the downregulation of c-Myc expression plays the role of inducing apoptosis and autophagy by MAC treatment in human leukemia cells. Conclusion: These findings significantly contributed to the understanding of the mechanism that accounts for the anticancer activity of MAC, and it may be novel anti-cancer therapeutic agents for leukemia cells.
Upregulation of AMPK by 4‐O‐methylascochlorin promotes autophagy via the HIF ‐1α expression
Seok, Ji‐,Young,Jeong, Yun‐,Jeong,Hwang, Soon‐,Kyung,Kim, Cheorl‐,Ho,Magae, Junji,Chang, Young‐,Chae John Wiley and Sons Inc. 2018 Journal of cellular and molecular medicine Vol.22 No.12
<P><B>Abstract</B></P><P>4‐O‐methylascochlorin (MAC) is a derivative of ascochlorin, a prenyl‐phenol compound antibiotic isolated from the fungus <I>Ascochyta viciae</I>. MAC induces caspase/poly (ADP‐ribose) polymerase‐mediated apoptosis in leukemia cells. However, the effects of MAC on autophagy in cancer cells and the underlying molecular mechanisms remain unknown. Here, we show that MAC induces autophagy in lung cancer cells. MAC significantly induced the expression of autophagy marker proteins including LC3‐II, Beclin1, and ATG7. MAC promoted AMP‐activated protein kinase (AMPK) phosphorylation and inhibited the phosphorylation of mammalian target of rapamycin (mTOR) and its downstream signalling proteins P70S6K and 4EBP1. The AMPK activator AICAR upregulated LC3‐II expression through the AMPK/mTOR pathway similar to the effects of MAC. MAC‐induced LC3‐II protein expression was slightly reduced in AMPK siRNA transfected cells. MAC upregulated hypoxia‐inducible factor‐1α (HIF‐1α) and BNIP3, which are HIF‐1α‐dependent autophagic proteins. Treatment with CoCl<SUB>2</SUB>, which mimics hypoxia, induced autophagy similar to the effect of MAC. The HIF‐1α inhibitor YC‐1 and HIF‐1α siRNA inhibited the MAC‐induced upregulation of LC3‐II and BNIP3. These results suggest that MAC induces autophagy via the AMPK/mTOR signalling pathway and by upregulating HIF‐1α and BNIP3 protein expression in lung cancer cells.</P>
Kang, Jeong Han,Kim, June-Ki,Park, Won-Hwan,Park, Kwan-Kyu,Lee, Tae-Sung,Magae, Junji,Nakajima, Hiroo,Kim, Cheorl-Ho,Chang, Young-Chae Wiley Subscription Services, Inc., A Wiley Company 2007 Journal of cellular biochemistry Vol.102 No.2
<P>The critical initiating event in atherogenesis involves the invasion of monocytes through the endothelial walls of arteries and the transformation of monocytes from macrophages into foam cells. Human THP-1 monocytic cells can be induced to differentiate into macrophages by phorbol myristate acetate (PMA) and can then be converted into foam cells by exposure to oxidized low-density lipoprotein (oxLDL). Also, during a chronic inflammatory response, monocytes/macrophages produce the 92-kDa matrix metalloproteinase-9 (MMP-9) that may contribute to the extravasation, migration, and tissue remolding capacities of the phagocytic cells. Here, we investigate the effect of ascochlorin (ASC), a prenylphenol antiviral compound from the fungus Ascochyta viciae, on oxLDL-induced MMP-9 expression and activity in human THP-1 macrophages. ASC reduced oxLDL-induced MMP-9 expression and activity in a time-dependent and dose-dependent manner. Also, an analysis of MMP-9 activity using pharmacologic inhibitors showed that ASC inhibits MMP-9 activity via the extracellular signal-regulated kinase 1 and kinase 2 pathways. Our results suggest that ASC may be useful as a potent clinical antiatherogenic agent, a topic of considerable interest in the biological chemistry of chemotherapeutic agents. J. Cell. Biochem. 102: 506–514, 2007. © 2007 Wiley-Liss, Inc.</P>