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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. Source


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. Source


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. Source

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