葡萄糖调节蛋白78（GRP78）通过激活肝细胞癌中的c-Src/LSF/胸苷合成酶（TS）轴赋予对5-氟尿嘧啶（5-FU）的抗性。
GRP78 confers the resistance to 5-FU by activating the c-Src/LSF/TS axis in hepatocellular carcinoma.
作者信息
Gu Yan-jiao, Li Hong-dan, Zhao Liang, Zhao Song, He Wu-bin, Rui Li, Su Chang, Zheng Hua-chuan, Su Rong-jian
机构信息
Pathology Department, The First Affiliated Hospital of Liaoning Medical College, Jinzhou, China.
Central Laboratory, Liaoning Medical College, Jinzhou, China.
出版信息
Oncotarget. 2015 Oct 20;6(32):33658-74. doi: 10.18632/oncotarget.5603.
5-FU is a common first-line chemotherapeutic drug for the treatment of hepatocellular carcinoma. However the development of acquired resistance to 5-FU confines its clinical usages. Although this phenomenon has been the subject of intense investigation, the exact mechanism of acquired resistance to 5-FU remains elusive. Here, we report that over-expression of GRP78 contributes to acquired resistance to 5-FU in HCC by up-regulating the c-Src/LSF/TS axis. Moreover, we found that the resistance to 5-FU conferred by GRP78 is mediated by its ATPase domain. The ATPase domain differentially increased the expression of LSF, TS and promoted the phosphorylation of ERK and Akt. We further identified that GRP78 interacts physically with c-Src through its ATPase domain and promotes the phosphorylation of c-Src, which in turn increases the expression of LSF in the nucleus. Together, GRP78 confers the resistance to 5-FU by up-regulating the c-Src/LSF/TS axis via its ATPase domain.
5-氟尿嘧啶（5-FU）是治疗肝细胞癌的常用一线化疗药物。然而，对5-FU获得性耐药的出现限制了其临床应用。尽管这一现象一直是深入研究的课题，但5-FU获得性耐药的确切机制仍不清楚。在此，我们报告称，葡萄糖调节蛋白78（GRP78）的过表达通过上调c-Src/LSF/胸苷酸合成酶（TS）轴，导致肝癌细胞对5-FU产生获得性耐药。此外，我们发现GRP78介导的对5-FU的耐药性是由其ATP酶结构域介导的。ATP酶结构域差异性地增加了LSF、TS的表达，并促进了细胞外信号调节激酶（ERK）和蛋白激酶B（Akt）的磷酸化。我们进一步确定，GRP78通过其ATP酶结构域与c-Src发生物理相互作用，并促进c-Src的磷酸化，进而增加细胞核中LSF的表达。总之，GRP78通过其ATP酶结构域上调c-Src/LSF/TS轴，赋予细胞对5-FU的耐药性。
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