Involvement of p38 mitogen-activated protein kinase in acquired gemcitabine-resistant human urothelial carcinoma sublines
| Autor: | Yeong-Shiau Pu, Shih Hsien Hsu, Chi-Yu Lu, Wei-Chi Hsu, Chien-Chih Chiu, Yu-Ting Kao, Chang-Shen Lin, Huei-Ting Hu, A-Mei Huang, Tzyh-Chyuan Hour |
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| Rok vydání: | 2014 |
| Předmět: |
MAPK/ERK pathway
Antimetabolites Antineoplastic endocrine system diseases Cell Survival Pyridines p38 mitogen-activated protein kinases Apoptosis Biology Deoxycytidine p38 Mitogen-Activated Protein Kinases Cyclin D1 Downregulation and upregulation Multidrug Resistance Protein 1 Cell Line Tumor Humans Protein kinase A Flavonoids Medicine(all) lcsh:R5-920 Carcinoma Transitional Cell Kinase Imidazoles p38 mitogen-activated protein kinase Drug Synergism Cell migration General Medicine Gemcitabine Urinary Bladder Neoplasms Drug Resistance Neoplasm Drug resistance Cancer research Urothelial carcinoma Drug Screening Assays Antitumor lcsh:Medicine (General) |
| Zdroj: | Kaohsiung Journal of Medical Sciences, Vol 30, Iss 7, Pp 323-330 (2014) |
| ISSN: | 1607-551X |
| DOI: | 10.1016/j.kjms.2014.03.004 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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