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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>
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.-
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>
Dai, Xiaoyun,Ahn, Kwang Seok,Wang, Ling Zhi,Kim, Chulwon,Deivasigamni, Amudha,Arfuso, Frank,Um, Jae-Young,Kumar, Alan Prem,Chang, Young-Chae,Kumar, Dhiraj,Kundu, Gopal C.,Magae, Junji,Goh, Boon Cher,H American Association for Cancer Research 2016 Molecular Cancer Therapeutics Vol.15 No.12
<P>Increasing evidence has indicated that epithelial-to-mesenchymal transition (EMT) at the advanced stage of liver cancer not only has the ability to self-renew and progress cancer, but also enables greater resistance to conventional chemo-and radiotherapies. Here, we report that ascochlorin (ASC), an isoprenoid antibiotic, could potentiate the cytotoxic effect of doxorubicin on HCCLM3, SNU387, SNU49, and SK-Hep-1 hepatocellular carcinoma cells, which had a predominantly mesenchymal signature with low expression of E-cadherin but high expression of N-cadherin. Co-administration of ASC reduced doxorubicin-induced invasion/migration and modulated EMT characteristics in mesenchymal cells. This process was probably mediated by the E-cadherin repressors Snail and Slug. In addition, ASC increased sensitivity to doxorubicin treatment by directly inhibiting STAT3 binding to the Snail promoter. We also observed that ASC significantly enhanced the effect of doxorubicin against tumor growth and inhibited metastasis in an HCCLM3_Luc orthotopic mouse model. Collectively, our data demonstrate that ASC can increase sensitivity to doxorubicin therapy and reverse the EMT phenotype via the downregulation of STAT3-Snail expression, which could form the basis of a novel therapeutic approach against hepatocellular carcinoma. (C) 2016 AACR.</P>
Cho, Hyun‐,Ji,Kang, Jeong‐,Han,Kim, Teoan,Park, Kwang‐,Kyun,Kim, Cheorl‐,Ho,Lee, In‐,Seon,Min, Kwan‐,Sik,Magae, Junji,Nakajima, Hiroo,Bae, Young‐,Seuk,Chang, Wiley Subscription Services, Inc., A Wiley Company 2009 Journal of cellular biochemistry Vol.107 No.2
<P><B>Abstract</B></P><P>Fibrosis in glomerulosclerosis causes progressive loss of renal function. Transforming growth factor (TGF)‐β, one of the major profibrotic cytokines, induces the synthesis of plasminogen activator inhibitor (PAI)‐1, a factor that plays a crucial role in the development of fibrosis. Here, we found that an isoprenoid antibiotic, ascofuranone, suppresses expression of profibrotic factors including matrix proteins and PAI‐1 induced by TGF‐β in renal fibroblasts. Ascofuranone selectively inhibits phosphorylation of epidermal growth factor receptor (EGFR), and downstream kinases such as Raf‐1, MEK‐1/2, and ERK‐1/2. PAI‐1 transcription also is suppressed by treatment with kinase inhibitors for MEK‐1/2 or EGFR, and with small interfering RNA for EGFR. Ascofuranone inhibits cellular metalloproteinase activity, and an inhibitor of metalloproteinases suppresses EGFR phosphorylation and PAI‐1 transcription. These results suggest that ascofuranone suppresses expression of profibrotic factors through the inhibition of an EGFR‐dependent signal transduction pathway activated by metalloproteinases. J. Cell. Biochem. 107: 335–344, 2009. © 2009 Wiley‐Liss, Inc.</P>