Publications (7)26.66 Total impact
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Article: Ascochlorin inhibits growth factor-induced HIF-1α activation and tumor-angiogenesis through the suppression of EGFR/ERK/p70S6K signaling pathway in human cervical carcinoma cells.
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ABSTRACT: Ascochlorin, a non-toxic prenylphenol compound derived from the fungus Ascochyta viciae, has been shown recently to have anti-cancer effects on various human cancer cells. However, the precise molecular mechanism of this anti-cancer activity remains to be elucidated. Here, we investigated the effects of ascochlorin on hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) expression in human epidermoid cervical carcinoma CaSki cells. Ascochlorin inhibited epidermal growth factor (EGF)-induced HIF-1α and VEGF expression through multiple potential mechanisms. First, ascochlorin selectively inhibited HIF-1α expression in response to EGF stimulation, but not in response to hypoxia (1% O(2)) or treatment with a transition metal (CoCl(2)). Second, ascochlorin inhibited EGF-induced ERK-1/2 activation but not AKT activation, both of which play essential roles in EGF-induced HIF-1α protein synthesis. Targeted inhibition of epidermal growth factor receptor (EGFR) expression using an EGFR-specific small interfering RNA (siRNA) diminished HIF-1α expression, which suggested that ascochlorin inhibits HIF-1α expression through suppression of EGFR activation. Finally, we showed that ascochlorin functionally abrogates in vivo tumor angiogenesis induced by EGF in a Matrigel plug assay. Our data suggest that ascochlorin inhibits EGF-mediated induction of HIF-1α expression in CaSki cells, providing a potentially new avenue of development of anti-cancer drugs that target tumor angiogenesis.Journal of Cellular Biochemistry 11/2011; 113(4):1302-13. · 2.87 Impact Factor -
Article: Ascochlorin suppresses TGF-β1-induced PAI-1 expression through the inhibition of phospho-EGFR in rat kidney fibroblast cells.
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ABSTRACT: Fibrosis is induced by the excessive and abnormal deposition of extracellular matrix (ECM) with various growth factors in tissues. Transforming growth factor-β1 (TGF-β1), the growth factor involved in fibrosis, modulates ECM synthesis and accumulation. TGF-β1 enhances the production of stimulators of ECM synthesis such as plasminogen activator inhibitor type 1 (PAI-1). As such, PAI-1 expression directly influences the proteolysis, invasion, and accumulation of ECM. It was shown in this study that ascochlorin, a prenylpenl antiobiotic, prevents the expression of profibrotic factors, such as PAI-1 and collagen type I, and that the TGF-β1-induced PAI-1 promoter activity is inhibited by ascochlorin. Ascochlorin abolishes the phosphorylation of the EGFR-MEK-ERK signaling pathway to regulate the TGF-β1-induced expression of PAI-1 without the inhibition of TβRII phosphorylation. Furthermore, the MEK inhibitor and EGFR siRNA block PAI-1 expression, and the Raf-1, MEK, and ERK signaling pathways for the regulation of PAI-1 expression. Ascochlorin suppresses the matrix metalloproteinases (MMPs) activity to activate the heparin-binding EGF-like growth factor (HB-EGF), to induce the phosphorylation of EGFR, and the MMPs inhibitor suppresses EGFR phosphorylation and the PAI-1 mRNA levels. These results suggest that ascochlorin prevents the expression of PAI-1 via the inhibition of an EGFR-dependent signal transduction pathway activated by MMPs.Molecular Biology Reports 09/2011; 39(4):4597-603. · 2.93 Impact Factor -
Article: 4-O-methylascochlorin, methylated derivative of ascochlorin, stabilizes HIF-1α via AMPK activation.
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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.Biochemical and Biophysical Research Communications 02/2011; 406(3):353-8. · 2.48 Impact Factor -
Article: Therapeutic Possibility of Ascofuranone for Autosomal Dominant Polycystic Kidney Disease - Response.
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ABSTRACT: ADPKD1 is mainly associated with mutations in the PKD1 gene encoding PC-1. PKD1 overexpression leads to increased expression of c-Myc and failed upregulation of p21(WAF1/CIP1), resulting in abnormal increase of RTE proliferation. c-Myc is reported as a major downstream effector of PKD1 signaling pathways and as a transcriptional repressor of p21(WAF1/CIP1). Because there is no effective treatment available for PKD, it is reasonable that downstream target genes of PKD, including c-Myc and p21(WAF1/CIP1), are considered as therapeutic targets for autosomal dominant polycystic kidney disease (ADPKD). In this regard, roscovintine is a salutary agent that has antiproliferative effects by increasing p21(WAF1/CIP1) in RTE. Rapamycin, a mTOR inhibitor, prevents cyst formation, and thus is also considered an effective agent against ADPKD. In our experience and that of our collaborative groups, ascofuranone has antitumor activities and various physiologic effects without inducing DNA damage in vivo and in vitro, similar with roscovintine, and it is a more safe and useful agent than other prenyl-phenol compounds, such as ascochlorin and derivatives, in animal studies. Ascofuranone activates p53 through phosphorylation of serine 392, involved in mitochondrial respiration, and enhances transcription of its downstream targets including p21(WAF1/CIP1) and Hdm2 (1). The induction of G(1) arrest by ascofuranone is associated with the p53-independent activation of p21(WAF1/CIP1) through disruption of c-Myc (2). R. Sears et al. showed that Myc protein stability was dependent on the Ras/Raf/ERK pathway or Ras-dependent PI3K pathway (3). ERK protects Myc from degradation by phosphorylation of serine 62; however, GSK-3, held in check by the action of AKT, degrades Myc by phosphorylation of threonine 58. Walz suggested that mTOR, the EGFR axis, and cAMP-activated B-Raf/ERK signaling pathways were the main routes of treatment for ADPKD (4). Ascofuranone suppressed PMA-induced activation of the Ras/Raf/ERK pathway involved in AP-1 activation (5) and selectively inhibited the phosphorylation of EGFR and downstream kinases such as Raf and ERK. These results consistently show that ascofuranone inhibits phosphorylation of ERK regardless of tissue types, as also shown by proteomic research. On the basis of our results, ascofuranone has appropriate properties that could be developed as a therapeutic tool for ADPKD as follows. First, ascofuranone induces cytostatic G(1) arrest without DNA damage. Second, ascofuranone not only upregulates p21(WAF1/CIP1) but also suppresses c-Myc, both proteins being therapeutic targets for ADPKD. Finally, ascofuranone inhibits the phosphorylation of ADPKD-related kinases including EGFR and ERK. Further study on the pharmacologic action of ascofuranone might provide a new therapeutic tool for ADPKD. Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed.Molecular Cancer Therapeutics 10/2010; · 5.23 Impact Factor -
Article: Ascochlorin, an isoprenoid antibiotic, induces G1 arrest via downregulation of c-Myc in a p53-independent manner.
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ABSTRACT: Numerous anti-cancer agents inhibit cell cycle progression via a p53-dependent mechanism; however, many of these carcinostatic substances are toxic. Here, we show that ascochlorin, an isoprenoid antibiotic, is a non-toxic anti-cancer agent that induces G1 arrest via the induction of p21(WAF1/CIP1) in a c-Myc, but not a p53, dependent manner. Ascochlorin has a broad spectrum of anti-tumor and anti-metastatic activities, but the molecular mechanism by which it inhibits cell cycle progression of cancer cells remains to be elucidated. We demonstrated that cytostatic G1 arrest by ascochlorin is mainly associated with the upregulation of p21(WAF1/CIP1), and the downregulation of c-Myc. Furthermore, we used a chromatin immunoprecipitation assay, RNA interference, and p53-deficient cells to verify that p21(WAF1/CIP1) induction by ascochlorin is related to transcriptional repression of c-Myc. Ascochlorin abolished pRB hyperphosphorylation, which resulted in the inactivation of E2F transcriptional activity. These results suggest that ascochlorin induces G1 arrest via the p53-independent suppression of c-Myc. Thus, we reveal a role for ascochlorin in inhibiting tumor growth via G1 arrest, and identify a novel regulatory mechanism for c-Myc.Biochemical and Biophysical Research Communications 07/2010; 398(1):68-73. · 2.48 Impact Factor -
Article: p53-independent induction of G1 arrest and p21WAF1/CIP1 expression by ascofuranone, an isoprenoid antibiotic, through downregulation of c-Myc.
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ABSTRACT: Ascofuranone has been shown to have antitumor activity, but the precise molecular mechanism by which it inhibits the proliferation of cancer cells remains unclear. Here, we study the effects of ascofuranone on cell cycle progression in human cancer cells and find that ascofuranone induces G(1) arrest without cytoxicity with upregulation of p53 and p21(WAF1/CIP1) while downregulating c-Myc and G(1) cyclins. Chromatin immunoprecipitation assay and RNA interference studies with cells deficient in p53 and p21 show that ascofuranone induces p21(WAF1/CIP1) expression and subsequent G(1) arrest through the release of p21(WAF1/CIP1) promoter from c-Myc-mediated transcriptional repression, independent of p53. Ascofuranone-induced p21(WAF1/CIP1) associates with CDK2 and prevents CDK2-cyclin E complex formation, leading to the inactivation of E2F transcriptional activity. These results suggest that ascofuranone upregulates p21(WAF1/CIP1) through p53-independent suppression of c-Myc expression, leading to cytostatic G(1) arrest. Thus, ascofuranone represents a unique natural antitumor compound that targets c-Myc independent of p53.Molecular Cancer Therapeutics 07/2010; 9(7):2102-13. · 5.23 Impact Factor -
Article: Ascochlorin activates p53 in a manner distinct from DNA damaging agents.
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ABSTRACT: 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.International Journal of Cancer 02/2009; 124(12):2797-803. · 5.44 Impact Factor
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Institutions
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2009–2011
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Catholic University of Daegu
- Department of Pathology
Taegu, Daegu, South Korea
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2010
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Central Research Institute of Electric Power Industry
Tokyo, Tokyo-to, Japan
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