Secretory clusterin contributes to oxaliplatin resistance by activating Akt pathway in hepatocellular carcinoma
Secretory clusterin contributes to oxaliplatin resistance by activating Akt pathway in hepatocellular carcinoma
复制标题
分泌性簇蛋白通过激活肝细胞癌中的 Akt 通路导致奥沙利铂耐药
DOI：
10.1111/cas.12088
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发表时间：
2013-03-01
期刊：
影响因子：
5.7
通讯作者：
Sun, Xueying
中科院分区：
文献类型：
--
作者：
Xiu, Peng;Dong, Xuesong;Sun, Xueying
分泌型聚集蛋白（sCLU）在许多癌症中表达，并与化疗耐药性有关。然而，sCLU在肝细胞癌（HCC）对奥沙利铂（OXA）（一种最近使用的第三代铂类药物）耐药中的作用仍不清楚。使用人HCC细胞产生耗尽或过表达sCLU和OXA抗性细胞的稳定转染子。sCLU的过表达消除了OXA诱导的细胞生长抑制和细胞凋亡，但sCLU的耗竭与OXA协同作用，通过调节参与线粒体凋亡途径的蛋白质，如Bcl-2，Bax，Bcl-xL和caspase-9，并影响Akt和GSK-3的磷酸化，抑制细胞生长并增强细胞凋亡。在OXA抗性细胞或过表达sCLU的稳定转染子中过表达sCLU显著增加磷酸化Akt。然而，特异性抑制Akt可增强sCLU过表达细胞对OXA的敏感性，但对sCLU表达无影响，提示sCLU与pAkt在HCC细胞中的调节作用可能是单向的。sCLU的表达水平影响OXA治疗免疫缺陷小鼠中建立的HCC肿瘤的疗效。结果表明sCLU通过激活Akt通路参与OXA耐药，提示sCLU可能是克服HCC OXA耐药的一个新的分子靶点。
Secretory clusterin (sCLU) is expressed in numerous cancers and is associated with the resistance to chemotherapy. However, the role of sCLU in the resistance of hepatocellular carcinoma (HCC) to oxaliplatin (OXA), a recently used third-generation platinum agent, remains unclear. The stable transfectants that are depleted of or overexpress sCLU and OXA-resistant cells were generated using human HCC cells. Overexpression of sCLU abrogated OXA-induced inhibition of cell growth and cell apoptosis, but depletion of sCLU synergized with OXA to inhibit cell growth and enhance cell apoptosis, by regulating proteins involved in mitochondrial apoptosis pathways, such as Bcl-2, Bax, Bcl-xL and caspase-9, and affecting phosphorylation of Akt and GSK-3. Overexpression of sCLU in either OXA-resistant cells or stable transfectants that overexpress sCLU significantly increased phosphorylated Akt. However, specific inhibition of Akt enhanced sensitivity of sCLU-overexpressing cells to OXA, but had no effect on sCLU expression, suggesting that the regulatory effects between sCLU and pAkt may be in a one-way manner in HCC cells. The expression levels of sCLU affected the therapeutic efficacy of OXA to treat HCC tumors established in immunodeficiency mice. The results have demonstrated that sCLU contributes to OXA resistance by activating Akt pathway, indicating that sCLU may be a novel molecular target for overcoming OXA resistance in HCC.