Characterization of mechanism involved in acquired resistance to sorafenib in a mouse renal cell cancer RenCa model
Characterization of mechanism involved in acquired resistance to sorafenib in a mouse renal cell cancer RenCa model
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DOI：
10.1007/s12094-013-1151-9
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发表时间：
2014-09-01
影响因子：
3.4
通讯作者：
Fujisawa, M.
中科院分区：
文献类型：
--
作者：
Harada, K.;Miyake, H.;Fujisawa, M.
为探讨肾细胞癌（RCC）对索拉非尼产生耐药的机制，以亲代小鼠RCC细胞系RenCa（RenCa/P）为研究对象，采用递增剂量的索拉非尼持续作用，建立了一株对索拉非尼产生耐药的细胞系RenCa/R，其IC 50值约为RenCa/P的6倍。Western blotting检测索拉非尼处理后细胞中几种分子表达的变化，并比较索拉非尼处理对细胞生长的影响。RenCa/P和RenCa/R对潜在的抗肾癌药物的敏感性无显著差异。在几种凋亡相关蛋白中，clusterin在RenCa/R中的表达显著高于RenCa/P。索拉非尼治疗后，磷酸化p44/42丝裂原活化蛋白激酶（MAPK）在RenCa/P中的表达水平显著降低，但在RenCa/R中的表达水平未显著降低。此外，用MAPK信号传导途径的特异性抑制剂的额外处理显著增加了RenCa/R对索拉非尼的敏感性，但不增加RenCa/P的敏感性。在没有索拉非尼处理的小鼠中，RenCa/P和RenCa/R的体内生长模式之间没有显著差异;但是，在此情况下，索拉非尼对RenCa/P肿瘤的生长抑制作用显著大于对RenCa/这些发现表明，在索拉非尼治疗过程中，clusterin的上调和MAPK通路的持续激活可能参与RCC对索拉非尼的耐药性的获得。
The objective of this study was to investigate the mechanism mediating the acquisition of a resistant phenotype to sorafenib in renal cell carcinoma (RCC).A parental mouse RCC cell line, RenCa (RenCa/P), was continuously exposed to increasing doses of sorafenib, and a cell line resistant to sorafenib (RenCa/R), showing an approximately sixfold higher IC50 than that of RenCa/P, was established. Changes in the expression of several molecules in these cell lines following sorafenib treatment were evaluated by western blotting, and the effects of sorafenib treatment on the in vivo growth patterns were compared.There were no significant differences in sensitivities to potential agents against RCC between RenCa/P and RenCa/R. Among several apoptosis-related proteins, the expression of clusterin in RenCa/R was significantly greater than that in RenCa/P. Following treatment with sorafenib, the expression level of phosphorylated p44/42 mitogen-activated protein kinase (MAPK) in RenCa/P, but not that in RenCa/R, was significantly decreased. Furthermore, additional treatment with a specific inhibitor of the MAPK signaling pathway significantly increased the sensitivity of RenCa/R to sorafenib, but not that of RenCa/P. There was no significant difference between the in vivo growth patterns of RenCa/P and RenCa/R in mice without sorafenib treatment; however, the growth inhibitory effect of sorafenib on the RenCa/P tumor was significantly greater than that on the RenCa/R tumor.These findings suggest that the upregulation of clusterin and continuous activation of the MAPK pathway during sorafenib treatment may be involved in the acquisition of a resistance to sorafenib in RCC.