Open AccessInvolvement of p38 mitogen‐activated protein kinase in acquired gemcitabine‐resistant human urothelial carcinoma sublines
Author(s) -
Kao YuTing,
Hsu WeiChi,
Hu HueiTing,
Hsu ShihHsien,
Lin ChangShen,
Chiu ChienChih,
Lu ChiYu,
Hour TzyhChyuan,
Pu YeongShiau,
Huang AMei
Publication year - 2014
Publication title -
the kaohsiung journal of medical sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.439
H-Index - 36
eISSN - 2410-8650
pISSN - 1607-551X
DOI - 10.1016/j.kjms.2014.03.004
Subject(s) - gemcitabine , cancer research , kinase , medicine , mapk/erk pathway , protein kinase a , cisplatin , p38 mitogen activated protein kinases , cancer , microbiology and biotechnology , biology , chemotherapy
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.