Bio Molecular Informatics Center

Bio, South Korea

Bio Molecular Informatics Center

Bio, South Korea

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Lee J.-Y.,Bio Molecular Informatics Center | Kim J.-K.,Bio Molecular Informatics Center | Cho M.-C.,Bio Molecular Informatics Center | Shin S.,Bio Molecular Informatics Center | And 2 more authors.
Journal of Natural Products | Year: 2010

We conducted in silico screening for human peroxisome proliferator- activated receptor gamma (hPPARγ) by performing an automated docking study with 450 flavonoids. Among the eight flavonoids as possible agonists of hPPARγ, only 3,6-dihydroxyflavone (4) increased the binding between PPARγ and steroid receptor coactivator-1 (SRC-1), approximately 5-fold, and showed one order higher binding affinity for PPARγ than a reference compound, indomethacin. The 6-hydroxy group of the A-ring of 3,6-dihydroxyflavone (4) participated in hydrogen-bonding interactions with the side chain of Tyr327, His449, and Tyr473. The B-ring formed a hydrophobic interaction with Leu330, Leu333, Val339, Ile341, and Met364. Therefore, 3,6-dihydroxyflavone is a potent agonist of hPPAR with cytotoxic effects on human cervical and prostate cancer cells. © 2010 The American Chemical Society and American Society of Pharmacognosy.


Lee S.,Bio Molecular Informatics Center | Kim J.-H.,Bio Molecular Informatics Center | Kim H.,Bio Molecular Informatics Center | Kang J. W.,Bio Molecular Informatics Center | And 7 more authors.
Immunology | Year: 2011

High-risk variants of human papillomavirus (HPV) induce cervical cancer by persistent infection, and are regarded as the principal aetiological factor in this malignancy. The pro-inflammatory cytokine interleukin-32 (IL-32) is present at substantial levels in cervical cancer tissues and in HPV-positive cervical cancer cells. In this study, we identified the mechanism by which the high-risk HPV-16 E7 oncogene induces IL-32 expression in cervical cancer cells. We used antisense transfection, over-expression, or knock-down of IL-32 to assess the effects of the HPV-16 E7 oncogene on IL-32 expression in cervical cancer cells. Cyclo-oxygenase 2 (COX-2) inhibitor treatment was conducted, and the expression levels, as well as the promoter activities, of IL-32 and COX-2 were evaluated in human HPV-positive cervical cancer cell lines. E7 antisense treatment reduced the expression levels and promoter activities of COX-2, which is constitutively expressed in HPV-infected cells. Constitutively expressed IL-32 was also inhibited by E7 antisense treatment. Moreover, IL-32 expression was blocked by the application of the selective COX-2 inhibitor, NS398, whereas COX-2 over-expression resulted in increased IL-32 levels. These results show that the high-risk variant of HPV induces IL-32 expression via E7-mediated COX-2 stimulation. However, E7 and COX-2 were down-regulated in the IL-32γ over-expressing cells and recovered by IL-32 small interfering RNA, indicating that E7 and COX-2 were feedback-inhibited by IL-32γ in cervical cancer cells. © 2010 The Authors. Immunology © 2010 Blackwell Publishing Ltd.


Lee K.M.,University of Minnesota | Lee K.M.,Seoul National University | Lee K.M.,Bio Molecular Informatics Center | Lee K.W.,University of Minnesota | And 10 more authors.
Cancer Prevention Research | Year: 2010

Nontoxic small molecules with multitargeting effects are believed to have potential in cancer prevention. Dietary phytochemicals were shown to exhibit cancer-preventive effects attributed to their antioxidant capacities. In this report, we show that the natural compound 5-deoxykaempferol (5-DK) exerts a chemopreventive effect on UVB-induced skin carcinogenesis by targeting multiple signaling molecules. 5-DK suppressed the UVB-induced expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor in mouse skin epidermal JB6 P+ cells. Moreover, 5-DK inhibited phosphorylation of MKK3/6, MKK4, and Akt, but had no effect on phosphorylation of Src, extracellular signal-regulated kinases, or ribosomal S6 kinase (RSK). However, 5-DK affected multiple targets by reducing Src, phosphoinositide 3-kinase (PI3K), and RSK2 activities. In particular, pull-down assays revealed that 5-DK specifically bound to and competed with ATP for binding with Src, PI3K, and RSK2. Exposure to 5-DK significantly suppressed UVB-induced tumorigenesis in mouse skin in a dose-dependent manner, and it inhibited the UVB-induced expression of COX-2, proliferating cell nuclear antigen, vascular endothelial growth factor, and matrix metalloproteinase-9. Our data suggest that 5-DK docks at the ATP-binding site of Src, PI3K, and RSK2. For RSK2, the ATP-binding site is located between the N- and C-lobes of the kinase domain. Taken together, our results indicate that 5-DK holds promise for the treatment of UVBinduced skin cancer by targeting Src, PI3K, and RSK2 signaling. © 2010 American Association for Cancer Research.


High-risk variants of human papillomavirus (HPV) induce cervical cancer by persistent infection, and are regarded as the principal aetiological factor in this malignancy. The pro-inflammatory cytokine interleukin-32 (IL-32) is present at substantial levels in cervical cancer tissues and in HPV-positive cervical cancer cells. In this study, we identified the mechanism by which the high-risk HPV-16 E7 oncogene induces IL-32 expression in cervical cancer cells. We used antisense transfection, over-expression, or knock-down of IL-32 to assess the effects of the HPV-16 E7 oncogene on IL-32 expression in cervical cancer cells. Cyclo-oxygenase 2 (COX-2) inhibitor treatment was conducted, and the expression levels, as well as the promoter activities, of IL-32 and COX-2 were evaluated in human HPV-positive cervical cancer cell lines. E7 antisense treatment reduced the expression levels and promoter activities of COX-2, which is constitutively expressed in HPV-infected cells. Constitutively expressed IL-32 was also inhibited by E7 antisense treatment. Moreover, IL-32 expression was blocked by the application of the selective COX-2 inhibitor, NS398, whereas COX-2 over-expression resulted in increased IL-32 levels. These results show that the high-risk variant of HPV induces IL-32 expression via E7-mediated COX-2 stimulation. However, E7 and COX-2 were down-regulated in the IL-32 over-expressing cells and recovered by IL-32 small interfering RNA, indicating that E7 and COX-2 were feedback-inhibited by IL-32 in cervical cancer cells.


Ginseng (Panax ginseng C.A. Meyer) has been used in Asian countries for the treatment of various diseases. However, the mechanisms of liquid Panax ginseng (LG) on allergic inflammatory response in epidermal growth factor (EGF)-stimulated human airway epithelial cells remain largely unclear.MUC5AC, cyclooxygenase (COX) 2, and matrix metalloproteinase (MMP) 9 expressions were measured using reverse transcription-polymerase chain reaction, Western blotting, and gelatin zymogram analyses in NCI-H292 cells. Extracellular signal-regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) protein levels were analyzed by Western blotting.To gain insight into the antiallergy effects of LG, we examined its influence on epidermal growth factor (EGF)-induced MMP-9 and COX-2 productions in NCI-H292 cells. LG was treated for 1 hour and then followed by EGF treatment for 24 hours into NCI-H292 cells. The decrease of COX-2 production was correlated with the reduced levels of proteins and mRNAs of inducible MMP-9 and MUC5AC. LG blocked upstream signaling of NF-kappa-B activation via inhibition of phosphorylations of inhibitor factor-kappa- B-alpha (I-kappa-B-alpha) and ERK. These results suggest that LG protects NCI-H292 cells from EGF-induced damage by down-regulation of COX-2, MMP-9, and MUC5AC gene expressions by blocking NF-kappa-B and ERK.LG modulates allergic inflammatory response in EGF-stimulated NCI-H292 human airway epithelial cells via inhibition of I-kappa-B-alpha and ERK.

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