title: Upregulation of RhoB via c-Jun N-terminal kinase signaling induces apoptosis of the human gastric carcinoma NUGC-3 cells treated with NSC12618.
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.
authors.affiliation: Medical Genome Research Center, Korea Research Institute of Bioscience and Biotechnology, Yuseong, Daejeon 305-806, Korea.
authors.forename: Bo-Kyung
authors.initials: BK
authors.lastname: Kim
authors.forename: Hwan Mook
authors.initials: HM
authors.lastname: Kim
authors.forename: Kyung-Sook
authors.initials: KS
authors.lastname: Chung
authors.forename: Dong-Myung
authors.initials: DM
authors.lastname: Kim
authors.forename: Song-Kyu
authors.initials: SK
authors.lastname: Park
authors.forename: Alexander
authors.initials: A
authors.lastname: Song
authors.forename: Kyoung-Jae
authors.initials: KJ
authors.lastname: Won
authors.forename: Kiho
authors.initials: K
authors.lastname: Lee
authors.forename: Yu-Kyoung
authors.initials: YK
authors.lastname: Oh
authors.forename: Kyeong
authors.initials: K
authors.lastname: Lee
authors.forename: Kyung-Bin
authors.initials: KB
authors.lastname: Song
authors.forename: Julian A
authors.initials: JA
authors.lastname: Simon
authors.forename: Gyoonhee
authors.initials: G
authors.lastname: Han
authors.forename: Misun
authors.initials: M
authors.lastname: Won
mesh_terms: D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D050881:E1A-Associated p300 Protein / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008715:Methionine / Q000031:analogs & derivatives / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects*; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D020743:rhoB GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C558305:4-hexadecanoyl-1,1-dimethylpiperazin-1-ium; D000873:Anthracenes; C096856:FTI 277; D010879:Piperazines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C432165:pyrazolanthrone; D008715:Methionine; D008156:Luciferases; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D020743:rhoB GTP-Binding Protein