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Bo-Kyung Kim,
Dong-Myung Kim,
Kyung-Sook Chung,
Song-Kyu Park,
Shin-Jung Choi,
Alexander Song,
Kiho Lee,
Chang-Woo Lee,
Kyung-Bin Song,
Gyoonhee Han, Julian Simon,
Hwan Mook Kim,
Misun Won
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ABSTRACT: We describe here a piperazine alkyl derivative, NSC126188, which induced apoptosis of HeLa cells by upregulating RhoB expression. NSC126188 caused multi-septation of fission yeast and hypersensitized a ∆rho3 mutant, which implicates the involvement of functional human homolog RhoB. The treatment of cells with NSC126188 induced apoptosis and a dramatic increase in RhoB expression. In addition, RhoB knockdown using siRNA rescued cells from apoptosis, indicating a crucial role of RhoB in NSC126188-induced apoptosis. In a reporter assay using luciferase and EGFP under control of the RhoB promoter, NSC126188 increased both luciferase activity and the expression of EGFP, implicating transcriptional activation of RhoB by NSC126188. Furthermore, NSC126188 demonstrated in vivo anti-tumor activity, inhibiting tumor growth by 66.8% in a nude mouse xenograft using PC-3 human prostate cancer cells. These results suggest that NSC126188 is a potential lead compound and that upregulation of RhoB is associated with NSC126188-induced apoptosis.
Investigational New Drugs 10/2011; 29(5):853-60. · 3.36 Impact Factor
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Bo-Kyung Kim,
Hwan Mook Kim,
Kyung-Sook Chung,
Dong-Myung Kim,
Song-Kyu Park,
Alexander Song,
Kyoung-Jae Won,
Kiho Lee,
Yu-Kyoung Oh,
Kyeong Lee,
Kyung-Bin Song, Julian A Simon,
Gyoonhee Han,
Misun Won
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ABSTRACT: RhoB expression is reduced in most invasive tumors, with loss of RhoB expression correlating significantly with tumor stage. Here, we demonstrate that upregulation of RhoB by the potent anticancer agent NSC126188 induces apoptosis of NUGC-3 human gastric carcinoma cells. The crucial role of RhoB in NSC126188-induced apoptosis is indicated by the rescue of NUGC-3 cells from apoptosis by knockdown of RhoB. In the presence of NSC126188, c-Jun N-terminal kinase (JNK) signaling was activated, and the JNK inhibitor SP600125 reduced RhoB expression and suppressed the apoptosis of NUGC-3 cells. Knockdowns of mitogen-activated protein kinase kinase (MKK) 4/7, JNK1/2 and c-Jun downregulated RhoB expression and rescued cells from apoptotic death in the presence of NSC126188. The JNK inhibitor SP600125 suppressed transcriptional activation of RhoB in the presence of NSC126188, as indicated by a reporter assay that used luciferase under the RhoB promoter. The ability of NSC126188 to increase luciferase activity through both the p300-binding site and the inverted CCAAT sequence (iCCAAT box) suggests that JNK signaling to upregulate RhoB expression is mediated through both the p300-binding site and the iCCAAT box. However, the JNK inhibitor SP600125 did not inhibit the upregulation of RhoB by farnesyltransferase inhibitor (FTI)-277. The p300-binding site did not affect activation of the RhoB promoter by FTI-277 in NUGC-3 cells, suggesting that the transcriptional activation of RhoB by NSC126188 occurs by a different mechanism than that reported for FTIs. Our data indicate that NSC126188 increases RhoB expression via JNK-mediated signaling through a p300-binding site and iCCAAT box resulting in apoptosis of NUGC-3 cells.
Carcinogenesis 11/2010; 32(3):254-61. · 5.70 Impact Factor
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Kyung-Sook Chung,
Nam-Hui Yim,
Seung-Hee Lee,
Shin-Jung Choi,
Kyung-Sun Hur,
Kwang-Lae Hoe,
Dong-Uk Kim,
Sondra Goehle,
Hyung-Bae Kim,
Kyung-Bin Song,
Hyang-Sook Yoo,
Ki-Hwan Bae, Julian Simon,
Misun Won
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ABSTRACT: The cell-based assay using yeast deletion mutants has been recognized as an efficient analysis to discover therapeutic compounds and reveal their mode of action. In this study, S. pombe deletion mutants-based HTS screening was carried out to identify potential anti-cancer agents. The NCI chemical library of 5700 compounds was screened using kit strains, which consisted of S. pombe mutants harboring deletions in genes involved in DNA repair and mitotic control. During the screening, we identified 40 compounds conferring growth inhibition of S. pombe. Their anti-tumorigenic properties were examined by phenotypic effect on S. pombe, flow cytometry and apoptosis analysis of human cancer. Here, we report hit compounds inducing apoptosis for development of anti-cancer agents suggesting that S. pombe deletion mutants are useful in identifying potential anti-cancer agents in human cancer therapeutics.
Investigational New Drugs 09/2008; 26(4):299-307. · 3.36 Impact Factor
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Kyung-Sook Chung,
Nam-Kyu Sun,
Seung-Hee Lee,
Hyun-Jee Lee,
Shin-Jung Choi,
Sun-Kyung Kim,
Ju-Hyun Song,
Young-Joo Jang,
Kyung-Bin Song,
Hyang-Sook Yoo, Julian Simon,
Misun Won
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ABSTRACT: Cerulenin, a fatty acid synthase (FAS) inhibitor, induces apoptosis of variety of tumor cells. To elucidate mode of action by cerulenin, we employed the proteomics approach using Schizosaccharomyces pombe. The differential protein expression profile of S. pombe revealed that cerulenin modulated the expressions of proteins involved in stresses and metabolism, including both ade10 and adk1 proteins. The nutrient supplementation assay demonstrated that cerulenin affected enzymatic steps transferring a phosphoribosyl group. This result suggests that cerulenin accumulates AMP and p-ribosyl-s-amino-imidazole carboxamide (AICAR) and reduces other necessary nucleotides, which induces feedback inhibition of enzymes and the transcriptional regulation of related genes in de novo and salvage adenine metabolic pathway. Furthermore, the deregulation of adenine nucleotide synthesis may interfere ribonucleotide reductase and cause defects in cell cycle progression and chromosome segregation. In conclusion, cerulenin induces apoptosis through deregulation of adenine nucleotide biosynthesis resulting in nuclear division defects in S. pombe.
Biochemical and Biophysical Research Communications 11/2006; 349(3):1025-31. · 2.48 Impact Factor
