Kao Yu-Ting, Hsu Wei-Chi, Hu Huei-Ting, Hsu Shih-Hsien, Lin Chang-Shen, Chiu Chien-Chih, Lu Chi-Yu, Hour Tzyh-Chyuan, Pu Yeong-Shiau, Huang A-Mei
Department of Medicine, Graduate Institute of Biochemistry, Kaohsiung Medical University, Kaohsiung, Taiwan.
Department of Medicine, Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
Kaohsiung J Med Sci. 2014 Jul;30(7):323-30. doi: 10.1016/j.kjms.2014.03.004. Epub 2014 Apr 17.
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.
对化疗药物的耐药性是癌症治疗中的主要挑战之一。更好地了解耐药性如何产生以及哪些分子改变与耐药性相关是开发新型有效治疗策略的关键。为了研究吉西他滨（Gem）耐药的潜在机制并提供可能的治疗选择，建立了三个吉西他滨耐药性尿路上皮癌亚系（NG0.6、NG0.8和NG1.0）。这些细胞对阿糖胞苷和顺铂具有交叉耐药性，但对5-氟尿嘧啶敏感。耐药细胞的[hENT1×dCK/RRM1×RRM2]mRNA比值较低。两种三磷酸腺苷结合盒蛋白ABCD1以及多药耐药蛋白1升高。此外，细胞周期蛋白D1、细胞周期蛋白依赖性激酶2和4上调，而细胞外信号调节激酶1/2和p38丝裂原活化蛋白激酶（MAPK）活性显著受到抑制。给予p38 MAPK抑制剂可显著降低NTUB1细胞对吉西他滨的敏感性，而给予细胞外信号调节激酶MAPK抑制剂则无此作用。此外，吉西他滨耐药亚系还表现出更高的迁移能力。在NG1.0细胞中，强制表达p38 MAPK可损害细胞迁移活性并增强对吉西他滨的敏感性。综上所述，这些结果表明在获得吉西他滨耐药性过程中涉及复杂机制，并提供了对开发治疗吉西他滨耐药肿瘤的治疗靶点可能重要的信息。
