title: Involvement of p38 mitogen-activated protein kinase in acquired gemcitabine-resistant human urothelial carcinoma sublines.
abstract: 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.
authors.affiliation: Department of Medicine, Graduate Institute of Biochemistry, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Yu-Ting
authors.initials: YT
authors.lastname: Kao
authors.affiliation: Department of Medicine, Graduate Institute of Biochemistry, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Wei-Chi
authors.initials: WC
authors.lastname: Hsu
authors.affiliation: Department of Medicine, Graduate Institute of Biochemistry, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Huei-Ting
authors.initials: HT
authors.lastname: Hu
authors.affiliation: Department of Medicine, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Shih-Hsien
authors.initials: SH
authors.lastname: Hsu
authors.affiliation: Department of Medicine, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan; Department of Biological Sciences, National Sun Yat-Sen University, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chang-Shen
authors.initials: CS
authors.lastname: Lin
authors.affiliation: Department of Biotechnology, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chien-Chih
authors.initials: CC
authors.lastname: Chiu
authors.affiliation: Department of Medicine, Graduate Institute of Biochemistry, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Chi-Yu
authors.initials: CY
authors.lastname: Lu
authors.affiliation: Department of Medicine, Graduate Institute of Biochemistry, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors.forename: Tzyh-Chyuan
authors.initials: TC
authors.lastname: Hour
authors.affiliation: Department of Urology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Yeong-Shiau
authors.initials: YS
authors.lastname: Pu
authors.affiliation: Department of Medicine, Graduate Institute of Biochemistry, Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address: amhuang@kmu.edu.tw.
authors.forename: A-Mei
authors.initials: AM
authors.lastname: Huang
mesh_terms: D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D017209:Apoptosis; D002295:Carcinoma, Transitional Cell / Q000188:drug therapy / Q000201:enzymology; D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005419:Flavonoids / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000201:enzymology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; D005419:Flavonoids; D007093:Imidazoles; D011725:Pyridines; D003841:Deoxycytidine; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; D000093542:Gemcitabine
keywords: Drug resistance; Gemcitabine; Urothelial carcinoma; p38 mitogen-activated protein kinase