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  • American Association for Cancer Research (AACR)  (3)
  • Kim, Tae-You  (3)
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  • American Association for Cancer Research (AACR)  (3)
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  • 1
    Online Resource
    Online Resource
    Abstract 1714: The role and mechanism of JAB1 as a therapeutic target in biliary tract cancer
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 1714-1714
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 1714-1714
    Abstract: Background: JAB1 (c-Jun activation domain binding protein-1) is a c-Jun coactivator, also known as COP9 signalosome subunit 5 (CSN5). Jab1 has an important role in cell proliferation and apoptosis. Overexpression of Jab1 is correlated with poor prognosis in various cancers. Biliary tract cancer (BTC) has a poor prognosis with a huge unmet medical need. The role of Jab1 has not been studied in BTC. We investigated the role and mechanism of Jab1 as a potential therapeutic target in BTC. Methods: We used 8 kinds of BTC cells and designed Jab1 siRNA. MTT assay and colony formation assay were done to determine growth inhibitory effect of Jab1 knockdown. Cell cycle analysis was done by FACS Calibur flow cytometer and cell migration was evaluated by wound healing assay. We used cycloheximide chase assay for measuring of protein half-life. Results: BTC cell lines showed high level of Jab1 expression. Among them, SNU478, SNU869 and SNU 1196 were indicated with especially higher level of Jab1 expression. Cell growth and proliferation of BTC cells were decreased by Jab1 knockdown. Depletion of Jab1 induced G1 arrest, as well as decreased CyclinD/CyclinA and increased p27. Cell migration was also inhibited by Jab1 knockdown. Inhibition of Jab1 showed the decrease of pSrc, pAkt. Interestingly, depletion of Jab1 led to the elevation of PTEN protein levels without change of PTEN mRNA levels. PTEN half-life was longer in Jab1 siRNA-transfected cells. Suppression of Jab1 increased the sensitivity of BTC cells to the cytotoxic chemotherapeutic agent. Conclusion: Suppression of Jab1 shows antitumor effects in BTC cells by inhibiting cell proliferation, migration, cell cycle and increase of chemosensitivity. Taken together, Jab1 might be a potential therapeutic target in BTC. Citation Format: Ah-Rong Nam, Kyo Hwa Kang, Ji Eun Park, Ju-Hee Bang, Ling Jin, Mei Hua Jin, Tae Yong Kim, Sae-Won Han, Sang-Hyun Song, Seock-Ah Im, Tae-You Kim, Do-Youn Oh, Yung-Jue Bang. The role and mechanism of JAB1 as a therapeutic target in biliary tract cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1714. doi:10.1158/1538-7445.AM2015-1714
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-1714
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 2
    Online Resource
    Online Resource
    Abstract 3599: Resistance mechanisms to HER2-targeting treatment in HER2-positive gastric cancer
    American Association for Cancer Research (AACR) ; 2015
    In:  Cancer Research Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3599-3599
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 75, No. 15_Supplement ( 2015-08-01), p. 3599-3599
    Abstract: Background: HER2 is the first validated therapeutic target in advanced gastric cancer (GC). Trastuzumab in combination with chemotherapy is used as a first-line treatment of GC. The resistance mechanisms to trastuzumab have not been widely known in GC. We investigated the resistance mechanisms to HER2-targeting agents in HER2-positive gastric cancer cells. Methods: SNU216 and NCI-N87 are HER2 amplified gastric cancer cells. Using these cells, we established trastuzumab-resistant cells (SNU216-HR, N87-HR) and dacomitinib (panHER inhibitor)-resistant cells (SNU216-PR). Acquired resistance of the established cell lines was verified by MTT assay and western blotting. We compared various receptor tyrosine kinase activities and protein expression levels between parental and resistant cells by RTK arrays and western blotting. We used many targeted agents (HER family inhibitor, PI3K inhibitor, mTOR inhibitor, MEK inhibitor, Src inhibitor, HSP90 inhibitor, etc) to overcome the resistance. Results: Resistant cells displayed more rapid growth rate and different morphology compared with parent cells. Resistant cells showed increased levels of pEGFR, pHER2, pHER3, pMET, pIGF1R, pAXL, pSTAT3, pAKT, pFAK, and TS compared with the parental cells in western blot. With the treatment of trastuzumab, HR cells showed elevated levels of EGFR, pHER2, AXL, pAXL, pMEK, pSRC, pSTAT3, pAKT, pERK and TS compared with the parental cells. With the treatment of dacominitib, PR cells showed elevated levels of pEGFR, pAXL, pIGF1R, pMEK, pSRC, pERK and TS compared with the parental cells in western blot. The RTK arrays also showed the similar findings. These resistant cells were more sensitive to Src inhibitor and PI3K inhibitor than parent cells. Conclusion: Resistance mechanisms to HER2-targeting strategy in gastric cancer include activation of HER, MET, FAK and Src pathway. Targeting these pathways is needed to overcome resistance. Citation Format: Kyo Hwa Kang, Ah-Rong Nam, Ji Eun Park, Ju-Hee Bang, Jin Ling, Mei Hua Jin, Tae Yong Kim, Sae-Won Han, Sang-Hyun Song, Seock-Ah Im, Tae-You Kim, Do-Youn Oh, Yung-Jue Bang. Resistance mechanisms to HER2-targeting treatment in HER2-positive gastric cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3599. doi:10.1158/1538-7445.AM2015-3599
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2015-3599
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2015
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
    Location Call Number Limitation Availability
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  • 3
    Online Resource
    Online Resource
    Src as a Therapeutic Target in Biliary Tract Cancer
    American Association for Cancer Research (AACR) ; 2016
    In:  Molecular Cancer Therapeutics Vol. 15, No. 7 ( 2016-07-01), p. 1515-1524
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 15, No. 7 ( 2016-07-01), p. 1515-1524
    Abstract: Src, a nonreceptor tyrosine kinase, is involved in a number of cancer-related signaling pathways and aberrantly activated in biliary tract cancer (BTC). This study aimed to elucidate the potential role of Src as a therapeutic target in BTC. We tested bosutinib, an orally active c-Src/Abl kinase inhibitor, alone or in combination with cytotoxic agents using 9 human BTC cell lines: SNU-245, SNU-308, SNU-478, SNU-869, SNU-1079, SNU-1196, HuCCT1, TFK-1, and EGI-1. Of these, SNU-308 and SNU-478 were relatively sensitive to bosutinib. Bosutinib abrogated phosphorylation of Src and its downstream molecules, and significantly increased G1 cell-cycle arrest and apoptosis. Bosutinib significantly inhibited cell migration and invasion and decreased epithelial–mesenchymal transition markers. Bosutinib combined with gemcitabine or cisplatin showed synergistic antiproliferative and antimigratory effects. In addition, this combination further inhibited phosphorylation of Src and its downstream molecules and decreased epithelial–mesenchymal transition marker expression compared with bosutinib alone. We established a SNU-478 xenograft model for in vivo experiments, because SNU-478 was more tumorigenic than SNU-308. Bosutinib combined with gemcitabine or cisplatin showed significantly more potent antitumor effects than bosutinib alone. Bosutinib combined with gemcitabine further decreased Ki-67 expression and Src phosphorylation, and further increased TUNEL expression. Our data suggest that Src might be a potential therapeutic target in BTC. Bosutinib demonstrated promising antitumor activity alone or in combination with gemcitabine or cisplatin in BTC cells, which supports further clinical development in patients with advanced BTC. Mol Cancer Ther; 15(7); 1515–24. ©2016 AACR.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-16-0013
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2016
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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