Hyun-Jun Kim

Hanyang University, Sŏul, Seoul, South Korea

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Publications (11)51.84 Total impact

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    ABSTRACT: Epidermal growth factor receptor (EGFR) is one of the most promising targets for cancer therapy. Here, we show the in vitro and in vivo anticancer effects and associated mechanisms of KO-202125, one of the synthesized aristolactam analogs, as a novel EGFR inhibitor, in EGFR-overexpressing cancer cell lines. KO-202125 showed more effective growth inhibition and apoptosis induction than gefitinib, a representative EGFR inhibitor, in various EGFR-overexpressing human cancers including estrogen receptor (ER)-negative MDA-MB-231 human breast cancer cells. Epidermal growth factor receptor phosphorylation at Tyr1068 was reduced and, consequently, the association of EGFR with p85 was decreased by KO-202125 treatment in MDA-MB-231 cell lines. This led to inactivation of the PI3K/Akt pathway, and consequently suppression of activation of the Wnt pathway and enhancement of the nuclear import of p27Kip1. KO-202125 treatment in nude mice injected with MDA-MB-231 cells showed inhibition of tumor growth without toxicity. Collectively, our results showed the possibility of KO-202125 as an effective therapy agent of EGFR-overexpressing cancer cells through reduced EGFR activity and downregulation of the Akt pathway.
    Cancer Science 03/2011; 102(3):marcover. · 3.48 Impact Factor
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    ABSTRACT: Epidermal growth factor receptor (EGFR) is one of the most promising targets for cancer therapy. Here, we show the in vitro and in vivo anticancer effects and associated mechanisms of KO-202125, one of the synthesized aristolactam analogs, as a novel EGFR inhibitor, in EGFR-overexpressing cancer cell lines. KO-202125 showed more effective growth inhibition and apoptosis induction than gefitinib, a representative EGFR inhibitor, in various EGFR-overexpressing human cancers including estrogen receptor (ER)-negative MDA-MB-231 human breast cancer cells. Epidermal growth factor receptor phosphorylation at Tyr1068 was reduced and, consequently, the association of EGFR with p85 was decreased by KO-202125 treatment in MDA-MB-231 cell lines. This led to inactivation of the PI3K/Akt pathway, and consequently suppression of activation of the Wnt pathway and enhancement of the nuclear import of p27Kip1. KO-202125 treatment in nude mice injected with MDA-MB-231 cells showed inhibition of tumor growth without toxicity. Collectively, our results showed the possibility of KO-202125 as an effective therapy agent of EGFR-overexpressing cancer cells through reduced EGFR activity and downregulation of the Akt pathway. (Cancer Sci 2011; 102: 597–604)
    Cancer Science 01/2011; 102(3):597 - 604. · 3.48 Impact Factor
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    ABSTRACT: Inhibitor of differentiation-1 (Id-1) has been shown to play an essential role in cell proliferation, invasion, migration, and anti-apoptosis. However, the effect of Id-1 in mammary gland development remains unknown. Here, we generated MMTV-Id-1 transgenic mice to study the role of Id-1 in mammary gland development. In virgin mice, Id-1 overexpression led to precocious development and delayed regression of terminal end buds (TEBs) compared with wild-type mice. The number of BrdU-positive cells and the expression of Wnt signaling molecules, β-catenin and cyclin D1, which regulate ductal extension and TEB formation in virgin, were statistically higher in Id-1 transgenic mice than in wild-type mice. Id-1 also had an effect on the formation and proliferation of lobuloalveolar structures during early and mid-pregnancy. Id-1 transgenic mice had more lobulated and prominent alveolar budding than wild-type mice and had significantly greater counts of lobuloalveolar structures in early pregnancy. The expression of BrdU, β-catenin, and cyclin D1 was also predominantly increased in Id-1 transgenic mice. Moreover, Id-1 transgenic mice showed delayed involution. Id-1 regulated the expression levels of anti-apoptotic Bcl-2 and pro-apoptotic Bax, and resulted in delay of apoptotic peak during postlactational involution. We also found that Id-1 was able to modulate expression of the regulators of Wnt/β-catenin signaling such as phospho-Akt, BMP2, FGF3, and RAR-β in tubuloalveolar development of mammary glands. Taken together, our results suggest that Id-1 plays a pivotal role in mammary gland development through Wnt signaling-mediated acceleration of precocity and alveologenesis and Bcl-2 family members-mediated delay of involution.
    Journal of Cellular Physiology 10/2010; 226(5):1340-52. · 4.22 Impact Factor
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    ABSTRACT: Mel-18, a polycomb group (PcG) protein, has been suggested as a tumor suppressor in human breast cancer. Previously, we reported that Mel-18 has antiproliferative activity in breast cancer cells. However, its functional mechanism has not been fully elucidated. Here, we investigated the role of Mel-18 in human breast cancer. We saw an inverse correlation between Mel-18 and phospho-Akt, which were expressed at low and high levels, respectively, in primary breast tumor tissues from 40 breast cancer patients. The effect of Mel-18 on cell growth was examined in two breast cancer cell lines, SK-BR-3 and T-47D, which express relatively low and high levels of endogenous Mel-18, respectively. On Mel-18 overexpression in SK-BR-3 cells, cell growth was attenuated and G(1) arrest was observed. Likewise, suppression of Mel-18 by antisense expression in T-47D cells led to enhanced cell growth and accelerated G(1)-S phase transition. In these cells, cyclin-dependent kinase (Cdk)-4 and Cdk2 activities were affected by Mel-18, which were mediated by changes in cyclin D1 expression and p27(Kip1) phosphorylation at Thr(157), but not by INK4a/ARF genes. The changes were both dependent on the phosphatidylinositol 3-kinase/Akt signaling pathway. Akt phosphorylation at Ser(473) was reduced by Mel-18 overexpression in SK-BR-3 cells and enhanced by Mel-18 suppression in T-47D cells. Akt-mediated cytoplasmic localization of p27(Kip1) was inhibited by Mel-18 in SK-BR-3 cells. Moreover, Mel-18 overexpression showed reduced glycogen synthase kinase-3beta phosphorylation, beta-catenin nuclear localization, T-cell factor/lymphoid enhancer factor promoter activity, and cyclin D1 mRNA level. Taken together, we established a linear relationship between Mel-18-->Akt-->G(1) phase regulators.
    Cancer Research 06/2008; 68(11):4201-9. · 9.28 Impact Factor
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    ABSTRACT: Wogonin is a plant monoflavonoid which has been reported to inhibit cell growth and/or induce apoptosis in various tumors. Herein, we investigated the in vitro and in vivo anticancer effects and associated mechanisms of wogonin in human breast cancer. Effects of wogonin were examined in estrogen receptor (ER)-positive and -negative human breast cancer cells in culture for proliferation, cell cycle progression, and apoptosis. The in vivo effect of oral wogonin was examined on tumor xenograft growth in athymic nude mice. The molecular changes associated with the biological effects of wogonin were analyzed by immunoblotting. Cell growth was attenuated by wogonin (50-200 microM), independently of its ER status, in a time- and concentration-dependent manner. Apoptosis was enhanced and accompanied by upregulation of PARP and Caspase 3 cleavages as well as proapoptotic Bax protein. Akt activity was suppressed and reduced phosphorylation of its substrates, GSK-3beta and p27, was observed. Suppression of Cyclin D1 expression suggested the downregulation of the Akt-mediated canonical Wnt signaling pathway. ER expression was downregulated in ER-positive cells, while c-ErbB2 expression and its activity were suppressed in ER-negative SK-BR-3 cells. Wogonin feeding to mice showed inhibition of tumor growth of T47D and MDA-MB-231 xenografts by up to 88% without any toxicity after 4 weeks of treatment. As wogonin was effective both in vitro and in vivo, our novel findings open the possibility of wogonin as an effective therapeutic and/or chemopreventive agent against both ER-positive and -negative breast cancers, particularly against the more aggressive and hormonal therapy-resistant ER-negative types.
    International Journal of Cancer 03/2008; 122(4):816-22. · 6.20 Impact Factor
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    ABSTRACT: Although increasing evidence supports the protective role of inhibitor of differentiation and DNA binding-1 (Id-1) against anticancer drug-induced apoptosis, the underlying molecular mechanisms seem to vary depending on the tumor system. Here, we examined the direct role of Id-1 in MCF-7 breast cancer cells by ectopically overexpressing Id-1 under serum-free condition, where the endogenous Id-1 expression was suppressed. Id-1 expression resulted in increased number of viable cells, reduced Bax expression, enhanced Bcl-2 expression, but no change in Bcl-xL expression. The expression of nuclear factor-kappaB (NF-kappaB) was augmented, while those of p53 and IkappaB were reduced. Such changes in p53 and NF-kappaB pathways were also functional, as assessed by real-time polymerase chain reactions and reporter assays of their known downstream targets, p21 and Il-6, as well as Bax and Bcl-2 genes. Finally, Id-1 played a protective role against taxol-induced apoptosis in breast cancer cells as assessed by MTT assay and apoptotic cell count upon taxol treatment (0-200 nM). Reduced Bax expression and enhanced Bcl-2 expression by Id-1 were also noted in the presence of taxol. Taken together, we present a molecular mechanism where Id-1 regulates p53 and NF-kappaB pathways, which in turn regulates Bax and Bcl-2 genes, thus providing a survival advantage under exogenous stress such as serum-free or taxol treatment in MCF-7 breast cancer cells. In this regard, inactivation of Id-1 may provide a potential therapeutic strategy leading to inhibition of breast cancer progression and anti-cancer drug resistance.
    Breast Cancer Research and Treatment 01/2008; 112(2):287-96. · 4.47 Impact Factor
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    ABSTRACT: Microarray analysis of RNA from d-galactosamine (GalN)-administered mouse livers was performed to establish a global gene expression profile during injury and regeneration stages at two different doses. A single dose of GalN at 266 or 26.6 mg/kg body weight was given intraperitoneally, and the liver samples were obtained after 6, 24, and 72 h. Histopathologic studies enabled the classification of the D-galactosamine effect into injury (6, 24 h) and regeneration (72 h) stages. By using the Applied Biosystems mouse genome survey microarray, a total of 7267 out of 33,315 (21.8%) genes were found to be statistically reliable at p<0.05 by two-way ANOVA, and 1469 (4.4%) probes at false discovery rate <5% by significance analysis of microarray. Among the statistically reliable clones by both analytical methods, 389 genes were differentially expressed when compared with non-treated control, with more than a 1.625-fold difference (which equals 0.7 in log(2) scale) at one or more GalN treatment conditions and with less than 1.625-fold difference at all three vehicle-treated conditions. Three hundred thirty six genes and 13 genes were identified as injury- and regeneration-specific genes, respectively, showing that most of the transcriptomic changes were seen during the injury stage. Furthermore, multiple genes involved in protein synthesis and degradation, mRNA processing and binding, and cell cycle regulation showed variable transcript levels upon acute GalN administration.
    Toxicology 10/2006; 227(1-2):136-44. · 4.02 Impact Factor
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    ABSTRACT: Microarray analysis of RNA from diclofenac-administered mouse livers was performed to establish a global gene expression profile during injury and recovery stages at two different doses. A single dose of diclofenac at 9.5 mg/kg or 0.95 mg/kg body weight was given orally, and the liver samples were obtained after 6, 24, and 72 h. Histopathologic studies enabled the classification of the diclofenac effect into injury (6, 24 h) and recovery (72 h) stages. By using the Applied Biosystems Mouse Genome Survey Microarray, a total of 7370 out of 33,315 (22.1%) genes were found to be statistically reliable at p<0.05 by two-way ANOVA, and 602 (1.8%) probes at false discovery rate <5% by Significance Analysis of Microarray. Among the statistically reliable clones by both analytical methods, 49 genes were differentially expressed with more than a 1.625-fold difference (which equals 0.7 in log(2) scale) at one or more treatment conditions. Forty genes and two genes were identified as injury- and recovery-specific genes, respectively, showing that most of the transcriptomic changes were seen during the injury stage. Furthermore, multiple genes involved in oxidative stress, eicosanoid synthesis, apoptosis, and ATP synthesis showed variable transcript levels upon acute diclofenac administration.
    Toxicology Letters 09/2006; 166(1):77-87. · 3.15 Impact Factor
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    ABSTRACT: Agonists to A3 adenosine receptor (A3AR) have been reported to inhibit cell growth and/or induce apoptosis in various tumors. We tested the effect of a novel A3AR agonist generically known as LJ-529 in breast cancer cells. Anchorage-dependent cell growth and in vivo tumor growth were attenuated by LJ-529, independently of its estrogen receptor (ER) alpha status. In addition, apoptosis was induced as evidenced by the activation of caspase-3 and c-poly(ADP)ribose polymerase. Furthermore, the Wnt signaling pathway was down-regulated and p27(kip) was induced by LJ-529. In ER-positive cells, the expression of ER was down-regulated by LJ-529, which might have additionally contributed to attenuated cell proliferation. In ER-negative, c-ErbB2-overexpressing SK-BR-3 cells, the expression of c-ErbB2 and its downstream extracellular signal-regulated kinase pathway were down-regulated by LJ-529. However, such effect of LJ-529 acted independently of its receptor because no A3AR was detected by reverse transcription-PCR in all four cell lines tested. In conclusion, our novel findings open the possibility of LJ-529 as an effective therapeutic agent against both ER-positive and ER-negative breast cancers, particularly against the more aggressive ER-negative, c-ErbB2-overexpressing types.
    Molecular Cancer Therapeutics 04/2006; 5(3):685-92. · 5.60 Impact Factor
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    ABSTRACT: Global gene expression profile was analyzed by microarray analysis of rat liver RNA after chronic carbon tetrachloride (CCl(4)) administration. Rats received 0.5 ml CCl(4)/kg three times a week, and the liver samples were obtained after 0, 30, 60, and 90 days of injection. Histopathologic studies of liver tissues enabled the classification of the CCl(4) effect into mild and severe fatty liver/steatosis (30 and 60 days, respectively) and fibrosis/cirrhosis (90 days) stages. The expression levels of 4,900 clones on a custom rat gene microarray were analyzed and the results were confirmed by semi-quantitative RT-PCR. Four hundred thirty-eight clones were differentially expressed with more than a 1.625-fold difference (which equals 0.7 in log2 scale) at one or more time points. Multiple genes involved in lipid metabolism and ribosome biogenesis showed differential transcript levels upon chronic CCl(4) administration, which was previously seen in acute rat model as well. In addition, a total of 149 clones were identified as fibrosis/cirrhosis-specific genes by either fold changes or Significance Analysis of Microarrays. In conclusion, we report microarray analysis results in rat liver upon chronic CCl(4) administration with a full chronological profile that not only covered fatty liver/steatosis but also later points of fibrosis/cirrhosis. These data will provide the insight of specific gene expression profiles that is implicated in the multistep process of fatty liver/steatosis and fibrosis/cirrhosis after chronic hepatotoxin exposure.
    Toxicology and Applied Pharmacology 12/2005; 208(3):242-54. · 3.98 Impact Factor
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    ABSTRACT: Microarray analysis of RNA from carbon tetrachloride (CCl4)-administered rat livers was performed at various time points to establish a global gene expression profile during injury and regeneration stages. A single dose of 1 ml/kg of CCl4 was given by ip injection, and the liver samples were obtained after 6, 24, 48 h, and 2 weeks. Histopathologic, biochemical, and immunohistochemical studies enabled the classification of the CCl4 effect into injury (6 and 24 h) and regeneration (48 h and 2 weeks) stages. The expression levels of 5180 clones on a custom rat gene microarray were analyzed and 587 clones yielded changeable gene expression on at least single time point. One hundred seventy-nine clones were classified as injury-specific clones, while 38 clones as regeneration-specific clones. Characteristic gene expression profiles could be associated with CCl4-induced gene expression with the disruption of lipid metabolism, which is known to cause the fatty liver induced by CCl4 treatment. In addition, induction of the transcripts for many ribosomal proteins was detected during the injury stage, particularly at the 24-h time point, despite the previous report of decreased protein synthesis rate upon CCl4 treatment. Several genes with known functions were also identified as CCl4-regulated genes. In conclusion, we established a global gene expression profile utilizing microarray analysis in rat liver upon acute CCl4 administration with a full chronological profile that not only covers injury stage but also later points of regeneration stage.
    Toxicology and Applied Pharmacology 09/2005; 206(1):27-42. · 3.98 Impact Factor