Radiation enhanced TGF-β signaling and the epithelial-to-mesenchymal trnasition (EMT) in syngeneic breast mouse models

Yhun Yhong Sheen(신윤용),So Yeon Park(박소연),Sin Ri Kim(김신리),Hyun Joo Nam(남현주),Jeong Hwa Jeon(전정화),Hee Won Jeong(정희원) 환경독성보건학회 2016 한국독성학회 심포지움 및 학술발표회 Vol.2016 No.6

Poster Presentations : Inhibition of CYP1a1 activity by COX - inhibitors in C57BL / 6 mouse and Hepa I cells

(Yhun Yhong Sheen),(Ja Young Kim),(Syrie Bang) 서울시립대학교 산업기술연구소 2002 국제학술SYMPOSIUM논문집 Vol.10 No.1

My Opinion on the Report of ILSI Korea on ‘System of Function Claims for the General Food’

Yhun Yhong Sheen 건강기능식품미래포럼 2021 건강기능식품미래포럼 학술지 Vol.1 No.4

None

Cinvited Review : Targeting the Transforming Growth Factor-β Signaling in Cancer Therapy

( Yhun Yhong Sheen ),( Min Jin Kim ),( Sang A Park ),( So Yeon Park ),( Jeong Seok Nam ) 한국응용약물학회 2013 Biomolecules & Therapeutics(구 응용약물학회지) Vol.21 No.5

TGF-β pathway is being extensively evaluated as a potential therapeutic target. The transforming growth factor-β (TGF-β) signaling pathway has the dual role in both tumor suppression and tumor promotion. To design cancer therapeutics successfully, it is important to understand TGF-β related functional contexts. This review discusses the molecular mechanism of the TGF-β pathway and describes the different ways of tumor suppression and promotion by TGF-β. In the last part of the review, the data on targeting TGF-β pathway for cancer treatment is assessed. The TGF-β inhibitors in pre-clinical studies, and Phase I and II clinical trials are updated.

Anti-Cancer Effect of IN-2001 in MDA-MB-231 Human Breast Cancer

( Yhun Yhong Sheen ),( Ki Eun Joung ),( Kyung Nan Min ),( Dae-kee Kim ) 한국응용약물학회 2012 Biomolecules & Therapeutics(구 응용약물학회지) Vol.20 No.3

In recent years, inhibition of HDACs has emerged as a potential strategy to reverse aberrant epigenetic changes associated with cancer, and several classes of HDAC inhibitors have been found to have potent and specifi c anticancer activities in preclinical studies. But their precise mechanism of action has not been elucidated. In this study, a novel synthetic inhibitor of HDAC, 3-(4-dimethylamino phenyl)-N-hydroxy-2-propenamide [IN-2001] was examined for its antitumor activity and the underlying molecular mechanisms of any such activity on human breast cancer cell lines. IN-2001 effectively inhibited cellular HDAC activity (IC50 = 0.585 nM) inMDA-MB-231 human breast cancer cells. IN-2001 caused a signifi cant dose-dependent inhibition of cell proliferation in estrogen receptor (ER) negative MDA-MB-231human breast cancer cells. Cell cycle analysis revealed that the growth inhibitory effects of IN-2001 might be attributed to cell cycle arrest at G0/G1 and/or G2/Mphase and subsequent apoptosis in human breast cancer cells. These events are accompanied by modulating several cell cycle and apoptosis regulatory genes such as CDK inhibitors p21WAF1 and p27KIP1 cyclin D1, and other tumor suppressor genes such as cyclin D2. Collectively, IN-2001 inhibited cell proliferation and induced apoptosis in human breast cancer cells and these fi ndings may provide new therapeutic approaches, combination of antiestrogen together with a HDAC inhibitor, in the hormonal therapy-resistant ER-negative breast cancers. In summary, our data suggest that this histone deacetylase inhibitor, IN-2001, is a novel promising therapeutic agent with potent antitumor effects against human breast cancers.

EW-7195, a novel inhibitor of ALKS kinase inhibits EMT and breast cancer metastasis to lung

Yhun Yhong, Sheen,Chul-Yong, Park,Jee-Yeon, Son,Cheng Hua, Jin,Jeong-Suk, Nam,Dae-Kee, Kim 梨花女子大學校 藥學硏究所 2012 藥學硏究論文集 Vol.- No.22

Recently, researchers are actively pursuing efforts to develop potent and selective ALK5 (TβRI) kinase inhibitors for clinical development. In this study, the authors examined a novel small molecule inhibitor of ALK5, 3-((4-([1,2,4]triazolo[1,5-a]pyridin-6-yl)-5-(6-methylpyridin-2-yl)-1H-imidazol-2-yl)methylamino)benzonitrile (EW-7195) to determine if it has potential for cancer treatment. The inhibitory effects of EW-7195 on TGF-β-induced Smad signaling and epithelial-to-mesenchymal transition (EMT) were investigated in mammary epithelial cells using luciferase reporter assays, immunoblotting, confocal microscopy and wound healing assays. In addition, the suppressive effects of EW-7195 on mammary cancer metastasis to lung were examined using a Balb/c xenograft and MMTV/cNeu transgenic mice model system. The novel ALK5 inhibitor, EW-7195, inhibited the TGF-β(1)-stimulated transcriptional activations of p3TP-Lux and pCAGA(12)-Luc. In addition, EW-7195 decreased phosphorylated Smad2 levels and the nuclear translocation of Smad2 increased by TGF-β(1). In addition, EW-7195 inhibited TGF-β(1)-induced EMT and wound healing of NMuMG cells. Furthermore, in xenografted Balb/c and MMTV/cNeu mice, EW-7195 inhibited metastasis to lung from breast tumours. The novel ALK5 inhibitor, EW-7195, efficiently inhibited TGF-β(1)-induced Smad signaling, EMT and breast tumour metastasis to the lung in vivo, demonstrating that EW-7195 has therapeutic potential for the breast cancer metastasis to the lung.

HDAC inhibitors regulate CYP3A4 gene expression in Hepatic cells

Yhun, Yhong Sheen...et al. 이화여자대학교 약학연구소 2003 藥學硏究論文集 Vol.- No.13

Cytochrome P450 3A4 (CYP3A4) is the most abundant CYPs in human liver, comprising approximately 30% of the total liver CYPs contents and is involved in the metabolism of more than 60% of currently used therapeutic drugs. The expression of CYP3A4 is induced by a variety of structurally unrelated xenobiotics including the antibiotic rifampicin and endogenous hormones, and might be mediated through steroid and xenobiotic receptor (SXR) system. The molecular mechanisms underlying regulation of CYP3A4 gene expression have not been understood. In order to gain the insight of the molecular mechanism of CYP3A4 gene expression, study has been undertaken to investigate if the histone deacetylation is involved in the regulation of CYP3A4 gene expression by proximal promoter or not. Also SXR was investigated to see if they were involved in the regulation of CYP3A4 proximal promoter activity. HepG2 or Hepa-I cells were transfected with a plasmid containing ∼1kb of the CYP3A4 proximal promoter region (863 to +64 bp) cloned in front of a reporter gene, luciferase, in the presence or absence of SXR or hERa. Transfected cells were treated with CYP3A4 inducers such as rifampicin, PCN and RU 486, or with estradiol, in order to examine the regulation of CYP3A4 gene expression in the presence or absence of trichostatin A (TSA). In HepG2 cells, CYP3A4 inducers and estradiol increased significantly the luciferase activity by CYP3A4 proximal promoter, only when TSA was co-treated after SXR cotransfection. In the case of Hepa-I cells, CYP3A4 inducers and estradiol increased modestly the luciferase activity when TSA was co-treated, but this incresment was not enhanced by SXR cotransfection in contrast to HepG2 cells. Taken together, these results indicated that the inhibition of histone deacetylation was required to SXR-mediated increase in CYP3A4 proximal promoter region when rifampicin, or PCN was treated. Further a transactivation by SXR may demand other species-specific transcription factors.

납(Lead)이 취외분비 기능에 미치는 영향

신윤용(Yhun Yhong Sheen),김원준(Won Joon Kim) 대한약리학회 1981 대한약리학잡지 Vol.17 No.1

No evidence has accumulated that lead compound is an essential component for biological function in animals. Lead is absorbed primarily through the epithelial mucosal cells in duodenum and the absorption can be enhanced by the substances which bind lead and increase its solubility. Iron, zinc and calcium ions, however, decrease the absorption of lead without affecting its solubility, probably by competing for shared absorptive receptors in the intestinal mucosa. Therefore, the absorption of lead is increased in iron deficient animals. Lead shows a strong affinity for ligands such as phosphate, cysteinyl and histidyl side chains of proteins, pterins and porphyrins. Hence lead can act on various active sites of enzymes, inhibiting the enzymes which has functional sulfhydryl groups. lead inhibits the activity of δ-aminolevulinic acid dehydratase for the biosynthesis of hemoproteins and cytochrome, which catalyzed the synthesis of monopyrrole prophobilinogen from δ-aminolevulinic acid. Accordingly lead decrease hepatic cytochrome p-450 content, resulting an inhibition of the activity of demethylase and hydroxylase in liver. Little informations are available on the effect of lead on digestive system although the catastrophic effects of lead intoxication are well documented. The present study was, therefore, attempted to investigate the effect of lead on pancreaticobiliary secretion in rats. Albino rats of both sexes weighing 170 ~ 230g were used for this study. The animals were divided into one control and three treated groups, i.e., control (physiologic saline 1.5ml/kg i.p.), lead acetate (l0μmole/kg/day i.p.), Pb(Ac)<Sub>2</sub> and EDTA(each 10μmole/kg/day i.p.), Pb(Ac)<Sub>2</sub> and FeSO<Sub>4</sub>(each l0μmole/kg/day hp). The pancreatico-biliary juice was collected under urethane anesthesia, and activities of amylase and lipase were determined by employing Sumner s and Cherry and Crandall s methods. The summarized results are follows. 1) In the experiment for acute toxicity of lead acetate, 20% of mortality was observed in rat treated with lead acetate as well as inhibition of the activity of amylase in the juice at the 3 rd day of the treatment. 2) No increases in body weight were observed in rats treated with lead acetate, while in control group the significant increases were observed. However, the body weights of animals were increased in the group lead acetate plus EDTA or FeSO<Sub>4</sub>. 3) Lead acetate decreased significantly the volume of pancreatico-biliary juice whereas additional treatment of EDTA and FeSO<Sub>4</sub> prevented it. 4) Total activity of amylase was markedly reduced due to lead acetate treatment, but no change was showed following additional treatment with EDTA and FeSO<Sub>4</sub>. 5) No changes in the cholate and lipase output were observed in rats treated with lead acetate as compared with that of control rats. 6) Increase in bilirubin output in rats treated with lead acetate was shown on the 2nd and 3rd weeks treatment. 7) In the case of in vitro experiment, lead acetate also markedly inhibited release of amylase from pancreatic fragment. 8) Histologic finding indicated that acini vacuolation was induced in the pancreatic tissue of rat treated with lead acete. From the above results, it might be concluded that lead acetate decreases the volume of pancreatico-biliary secretion and inhibits the amylase activity, by acting directly on pancreatic cells.

안티에스트로젠이 MCF - 7 사람 유방암 세포에서 분비하는 단백질 합성에 미치는 영향

신윤용 ( Yhun Yhong Sheen ) 생화학분자생물학회 1993 BMB Reports Vol.26 No.8

Antiestrogen, such as tamoxifen, selectively increased the production of secreted protein of 37,000 molecular weight (Mr) in estrogen receptor positive human breast cancer MCF7 cells but not in estrogen receptor negative MDA-MB-231 cells, and the production of this protein by antiestrogen was inhibited by concomitant estradiol treatment. Proteins were detected by [^(35)S]methionine and [^(35)S]cysteine labeling of the cells and analysis of proteins by sodium dodecyl sulfate-polyacrylamide gels and autoradiography. Enhanced production of 37,000 Mr protein was observed within 6 h of antiestrogen treatment, with maximal synthesis seen at 1∼2 days when this protein represents about 6% of the total radiolabeled secreted proteins. This protein was stimulated maximally by 10^(-8) M traps-hydroxytamoxifen or LY 117018 or 10^(-6) M tamoxifen, and its antiestrogen specificity was seen by the fact that transtamoxifen increased this protein, whereas cis-tamoxifen, an estrogen, does not. Interestingly, the basal level of synthesis of the 37,000 Mr protein was high in the absence of estrogen and was then stimulated only minimally by the addition of antiestrogen, suggesting that this protein was clearly produced as an estrogen antagonistic protein. Amino acid incorporation conducted in the presence of tunicamycin and endoglycosidase H indicated that this protein was glycoprotein. This protein might serve as an useful marker for antiestrogen action in MCF-7 human breast cancer cells.

에스트로젠이 MCF - 7 사람 유방암 세포에서 분비하는 단백질 합성에 미치는 영향

신윤용 ( Yhun Yhong Sheen ) 생화학분자생물학회 1993 BMB Reports Vol.26 No.8

Estrogen selectively increased the production of sercreted proteins of 32,000 Mr, 52,000 Mr, 160,000 Mr in estrogen receptor positive human breast cancer MCF-7 cells but not in estrogen receptor negative MDA-MB-231 cells, and the production of these proteins by estrogen was inhibited by concomitant antiestrogen treatment. Proteins were detected by [^(35)S]methionine and [^(35)S]cysteine labeling of the cells and analysis of proteins by sodium dodecyl sulfate-polyacrylamide gels and autoradiography. Enhanced production of 32,000 Mr, 52,000 Mr, 160,000 Mr proteins were observed within 6 hours of estrogen treatment, with maximal synthesis seen at 2 days. When cells were grown in estrogen free condition, i.e. in charcoaldextran treated serum in medium lacking the estrogen phenol red, the basal level of the 32,000 Mr protein was extremely low, and estrogen stimulation results in 10-fold increase in the production of this protein. Amino acid incorporation conducted in the presence of tunicamycin and endoglycosidase H indicates that this protein is glycoprotein. This protein might serve as an useful marker for estrogen action and may be involved in estrogen modulation of cell proliferation and/or cell function.