Upregulation of RhoB via c-Jun N-terminal kinase signaling induces apoptosis of the human gastric carcinoma NUGC-3 cells treated with NSC12618

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

Research output: Contribution to journalArticle

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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.

Original languageEnglish
Pages (from-to)254-261
Number of pages8
JournalCarcinogenesis
Volume32
Issue number3
DOIs
Publication statusPublished - 2011 Mar 10

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4-hexadecanoyl-1,1-dimethylpiperazin-1-ium
JNK Mitogen-Activated Protein Kinases
Stomach
Up-Regulation
Apoptosis
Carcinoma
Phosphotransferases
Binding Sites
Farnesyltranstransferase
Luciferases
Transcriptional Activation
MAP Kinase Kinase 7
MAP Kinase Kinase 4
Sequence Inversion
Antineoplastic Agents

All Science Journal Classification (ASJC) codes

  • Cancer Research

Cite this

Kim, Bo Kyung ; Kim, Hwan Mook ; Chung, Kyung Sook ; Kim, Dong Myung ; Park, Song Kyu ; Song, Alexander ; Won, Kyoung Jae ; Lee, Kiho ; Oh, Yu Kyoung ; Lee, Kyeong ; Song, Kyung Bin ; Simon, Julian A. ; Han, Gyoonhee ; Won, Misun. / Upregulation of RhoB via c-Jun N-terminal kinase signaling induces apoptosis of the human gastric carcinoma NUGC-3 cells treated with NSC12618. In: Carcinogenesis. 2011 ; Vol. 32, No. 3. pp. 254-261.
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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.",
author = "Kim, {Bo Kyung} and Kim, {Hwan Mook} and Chung, {Kyung Sook} and Kim, {Dong Myung} and Park, {Song Kyu} and Alexander Song and Won, {Kyoung Jae} and Kiho Lee and Oh, {Yu Kyoung} and Kyeong Lee and Song, {Kyung Bin} and Simon, {Julian A.} and Gyoonhee Han and Misun Won",
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Kim, BK, Kim, HM, Chung, KS, Kim, DM, Park, SK, Song, A, Won, KJ, Lee, K, Oh, YK, Lee, K, Song, KB, Simon, JA, Han, G & Won, M 2011, 'Upregulation of RhoB via c-Jun N-terminal kinase signaling induces apoptosis of the human gastric carcinoma NUGC-3 cells treated with NSC12618', Carcinogenesis, vol. 32, no. 3, pp. 254-261. https://doi.org/10.1093/carcin/bgq244

Upregulation of RhoB via c-Jun N-terminal kinase signaling induces apoptosis of the human gastric carcinoma NUGC-3 cells treated with NSC12618. / Kim, Bo Kyung; Kim, Hwan Mook; Chung, Kyung Sook; Kim, Dong Myung; Park, Song Kyu; Song, Alexander; Won, Kyoung Jae; Lee, Kiho; Oh, Yu Kyoung; Lee, Kyeong; Song, Kyung Bin; Simon, Julian A.; Han, Gyoonhee; Won, Misun.

In: Carcinogenesis, Vol. 32, No. 3, 10.03.2011, p. 254-261.

Research output: Contribution to journalArticle

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T1 - Upregulation of RhoB via c-Jun N-terminal kinase signaling induces apoptosis of the human gastric carcinoma NUGC-3 cells treated with NSC12618

AU - Kim, Bo Kyung

AU - Kim, Hwan Mook

AU - Chung, Kyung Sook

AU - Kim, Dong Myung

AU - Park, Song Kyu

AU - Song, Alexander

AU - Won, Kyoung Jae

AU - Lee, Kiho

AU - Oh, Yu Kyoung

AU - Lee, Kyeong

AU - Song, Kyung Bin

AU - Simon, Julian A.

AU - Han, Gyoonhee

AU - Won, Misun

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N2 - 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.

AB - 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.

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