JNK-mediated transcriptional upregulation of RhoB is critical for apoptosis of HCT-116 colon cancer cells by a novel diarylsulfonylurea derivative = 신규 diarylsulfonylurea 유도체의 세포사멸과정에서의 RhoB 발현과 JNK 신호의 중요성

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Title
JNK-mediated transcriptional upregulation of RhoB is critical for apoptosis of HCT-116 colon cancer cells by a novel diarylsulfonylurea derivative = 신규 diarylsulfonylurea 유도체의 세포사멸과정에서의 RhoB 발현과 JNK 신호의 중요성
Author(s)
D M Kim; Mi Sun WonKyung Sook ChungSemi Kim; H J Yim; S H Jung; S W Jeong
Bibliographic Citation
Apoptosis, vol. 15, no. 12, pp. 1540-1548
Publication Year
2010
Abstract
Diarylsulfonylureas are potent antitumor agents that have been tested in clinical trials. However, detailed mechanisms of their apoptotic activity remain unclear. Here, we report a new diarylsulfonylurea derivative, LB2A, that upregulates RhoB, thereby inducing potent apoptosis in HCT-116 human colon cancer cells independently of p53 status. LB2A decreased procaspase-3, increased phospho-JNK, and cleaved PARP, leading to apoptosis of HCT-116 cells. Prior treatment of HCT-116 cells with the JNK inhibitor SP600125 and the RNA synthesis inhibitor DRB blocked apoptosis, implying that JNK activation and mRNA production are important for apoptosis by LB2A. Western blotting, RT-PCR, and RhoB-promoter luciferase reporter assays revealed that LB2A increased RhoB via JNK-mediated transcriptional activation. LB2A decreased HDAC1 and increased acetyl-H3, both of which activate the RhoB promoter and were blocked by SP600125. Ectopic expression of RhoB induced apoptosis of HCT-116 cells, suggesting that RhoB is critical for the anti-cancer activity of LB2A in human colon cancer cells. LB2A also exhibited potent tumor growth inhibition of HCT-116 cells in vivo using a mouse xenograft assay. Taken together, these results show that LB2A induces apoptosis of HCT-116 cells via JNK-mediated transcriptional upregulation of RhoB and may therefore provide a potential therapy for human colon cancer.
Keyword
Anti-cancer agentApoptosisDiarylsulfonylureaHDAC1RhoBSAPK/JNK
ISSN
1360-8185
Publisher
Springer
DOI
http://dx.doi.org/10.1007/s10495-010-0531-7
Type
Article
Appears in Collections:
Division of Biomedical Research > Personalized Genomic Medicine Research Center > 1. Journal Articles
Division of Research on National Challenges > 1. Journal Articles
Division of Biomedical Research > Microbiome Convergence Research Center > 1. Journal Articles
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