JNK-mediated transcriptional upregulation of RhoB is critical for apoptosis of HCT-116 colon cancer cells by a novel diarylsulfonylurea derivative

• Published in: Apoptosis (London) 2010-12, Vol.15 (12), p.1540-1548
• Main Authors: Kim, Dong-Myung, Won, Misun, Chung, Chung-Sook, Kim, Semi, Yim, Hyeon Joo, Jung, Sang-Hun, Jeong, ShinWu
• Format: Article
• Language: English
• Subjects: Animals; Anthracenes - pharmacology; Anti-cancer agent; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - therapeutic use; apoptosis; Apoptosis - drug effects; Biochemistry; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cell Biology; Cell Line, Tumor; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; Diarylsulfonylurea; Dichlororibofuranosylbenzimidazole - pharmacology; Female; Flow Cytometry; HDAC1; Humans; Intracellular Signaling Peptides and Proteins - metabolism; JNK Mitogen-Activated Protein Kinases - metabolism; Luciferases - analysis; Mice; Mice, Inbred BALB C; Neoplasm Transplantation; Oncology; Original Paper; Plasmids; RhoB; rhoB GTP-Binding Protein - metabolism; SAPK/JNK; Signal Transduction - drug effects; Sulfonylurea Compounds - chemistry; Sulfonylurea Compounds - pharmacology; Sulfonylurea Compounds - therapeutic use; Transcription, Genetic - drug effects; Up-Regulation - drug effects; Virology
• ISSN: 1360-8185; 1573-675X
• DOI: 10.1007/s10495-010-0531-7

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.