Involvement of p38 mitogen-activated protein kinase in acquired gemcitabine-resistant human urothelial carcinoma sublines
Resistance to chemotherapeutic drugs is one of the major challenges in the treatment of cancer. A better understanding of how resistance arises and what molecular alterations correlate with resistance is the key to developing novel effective therapeutic strategies. To investigate the underlying mech...
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doaj-0905662aa3be47a18a9b6d9bc9bd9d322020-11-25T00:12:32ZengWileyKaohsiung Journal of Medical Sciences1607-551X2014-07-0130732333010.1016/j.kjms.2014.03.004Involvement of p38 mitogen-activated protein kinase in acquired gemcitabine-resistant human urothelial carcinoma sublinesYu-Ting Kao0Wei-Chi Hsu1Huei-Ting Hu2Shih-Hsien Hsu3Chang-Shen Lin4Chien-Chih Chiu5Chi-Yu Lu6Tzyh-Chyuan Hour7Yeong-Shiau Pu8A-Mei Huang9Department of Medicine, Graduate Institute of Biochemistry, Kaohsiung Medical University, Kaohsiung, TaiwanDepartment of Medicine, Graduate Institute of Biochemistry, Kaohsiung Medical University, Kaohsiung, TaiwanDepartment of Medicine, Graduate Institute of Biochemistry, Kaohsiung Medical University, Kaohsiung, TaiwanDepartment of Medicine, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, TaiwanDepartment of Medicine, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, TaiwanDepartment of Biotechnology, Kaohsiung Medical University, Kaohsiung, TaiwanDepartment of Medicine, Graduate Institute of Biochemistry, Kaohsiung Medical University, Kaohsiung, TaiwanDepartment of Medicine, Graduate Institute of Biochemistry, Kaohsiung Medical University, Kaohsiung, TaiwanDepartment of Urology, College of Medicine, National Taiwan University, Taipei, TaiwanDepartment of Medicine, Graduate Institute of Biochemistry, Kaohsiung Medical University, Kaohsiung, TaiwanResistance to chemotherapeutic drugs is one of the major challenges in the treatment of cancer. A better understanding of how resistance arises and what molecular alterations correlate with resistance is the key to developing novel effective therapeutic strategies. To investigate the underlying mechanisms of gemcitabine (Gem) resistance and provide possible therapeutic options, three Gem-resistant urothelial carcinoma sublines were established (NG0.6, NG0.8, and NG1.0). These cells were cross-resistant to arabinofuranosyl cytidine and cisplatin, but sensitive to 5-fluorouracil. The resistant cells expressed lower values of [hENT1 × dCK/RRM1 × RRM2] mRNA ratio. Two adenosine triphosphate-binding cassette proteins ABCD1 as well as multidrug resistance protein 1 were elevated. Moreover, cyclin D1, cyclin-dependent kinases 2 and 4 were upregulated, whereas extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase (MAPK) activity were repressed significantly. Administration of p38 MAPK inhibitor significantly reduced the Gem sensitivity in NTUB1 cells, whereas that of an extracellular signal-regulated kinase MAPK inhibitor did not. Furthermore, the Gem-resistant sublines also exhibited higher migration ability. Forced expression of p38 MAPK impaired the cell migration activity and augmented Gem sensitivity in NG1.0 cells. Taken together, these results demonstrate that complex mechanisms were merged in acquiring Gem resistance and provide information that can be important for developing therapeutic targets for treating Gem-resistant tumors.http://www.sciencedirect.com/science/article/pii/S1607551X14000746Drug resistanceGemcitabinep38 mitogen-activated protein kinaseUrothelial carcinoma |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Yu-Ting Kao Wei-Chi Hsu Huei-Ting Hu Shih-Hsien Hsu Chang-Shen Lin Chien-Chih Chiu Chi-Yu Lu Tzyh-Chyuan Hour Yeong-Shiau Pu A-Mei Huang |
spellingShingle |
Yu-Ting Kao Wei-Chi Hsu Huei-Ting Hu Shih-Hsien Hsu Chang-Shen Lin Chien-Chih Chiu Chi-Yu Lu Tzyh-Chyuan Hour Yeong-Shiau Pu A-Mei Huang Involvement of p38 mitogen-activated protein kinase in acquired gemcitabine-resistant human urothelial carcinoma sublines Kaohsiung Journal of Medical Sciences Drug resistance Gemcitabine p38 mitogen-activated protein kinase Urothelial carcinoma |
author_facet |
Yu-Ting Kao Wei-Chi Hsu Huei-Ting Hu Shih-Hsien Hsu Chang-Shen Lin Chien-Chih Chiu Chi-Yu Lu Tzyh-Chyuan Hour Yeong-Shiau Pu A-Mei Huang |
author_sort |
Yu-Ting Kao |
title |
Involvement of p38 mitogen-activated protein kinase in acquired gemcitabine-resistant human urothelial carcinoma sublines |
title_short |
Involvement of p38 mitogen-activated protein kinase in acquired gemcitabine-resistant human urothelial carcinoma sublines |
title_full |
Involvement of p38 mitogen-activated protein kinase in acquired gemcitabine-resistant human urothelial carcinoma sublines |
title_fullStr |
Involvement of p38 mitogen-activated protein kinase in acquired gemcitabine-resistant human urothelial carcinoma sublines |
title_full_unstemmed |
Involvement of p38 mitogen-activated protein kinase in acquired gemcitabine-resistant human urothelial carcinoma sublines |
title_sort |
involvement of p38 mitogen-activated protein kinase in acquired gemcitabine-resistant human urothelial carcinoma sublines |
publisher |
Wiley |
series |
Kaohsiung Journal of Medical Sciences |
issn |
1607-551X |
publishDate |
2014-07-01 |
description |
Resistance to chemotherapeutic drugs is one of the major challenges in the treatment of cancer. A better understanding of how resistance arises and what molecular alterations correlate with resistance is the key to developing novel effective therapeutic strategies. To investigate the underlying mechanisms of gemcitabine (Gem) resistance and provide possible therapeutic options, three Gem-resistant urothelial carcinoma sublines were established (NG0.6, NG0.8, and NG1.0). These cells were cross-resistant to arabinofuranosyl cytidine and cisplatin, but sensitive to 5-fluorouracil. The resistant cells expressed lower values of [hENT1 × dCK/RRM1 × RRM2] mRNA ratio. Two adenosine triphosphate-binding cassette proteins ABCD1 as well as multidrug resistance protein 1 were elevated. Moreover, cyclin D1, cyclin-dependent kinases 2 and 4 were upregulated, whereas extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase (MAPK) activity were repressed significantly. Administration of p38 MAPK inhibitor significantly reduced the Gem sensitivity in NTUB1 cells, whereas that of an extracellular signal-regulated kinase MAPK inhibitor did not. Furthermore, the Gem-resistant sublines also exhibited higher migration ability. Forced expression of p38 MAPK impaired the cell migration activity and augmented Gem sensitivity in NG1.0 cells. Taken together, these results demonstrate that complex mechanisms were merged in acquiring Gem resistance and provide information that can be important for developing therapeutic targets for treating Gem-resistant tumors. |
topic |
Drug resistance Gemcitabine p38 mitogen-activated protein kinase Urothelial carcinoma |
url |
http://www.sciencedirect.com/science/article/pii/S1607551X14000746 |
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