Upregulation of the antiapoptotic factor Livin contributes to cisplatin resistance in colon cancer cells
Upregulation of the antiapoptotic factor Livin contributes to cisplatin resistance in colon cancer cells
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DOI：
10.1007/s13277-012-0596-8
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发表时间：
2013-04-01
期刊：
影响因子：
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通讯作者：
Sun, Xiao-Feng
中科院分区：
文献类型：
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作者：
Ding, Zhen-Yu;Liu, Gui-Hong;Sun, Xiao-Feng
抗凋亡因子 Livin 被认为对于肿瘤进展和不同类型肿瘤的不良预后至关重要。然而，关于其在结肠癌中的表达和生物学功能的报道非常有限。在这里，我们在存在或不存在顺铂（用作模型试剂）的情况下检查了四种结肠癌细胞系（HCT116、RKO、KM12C 和 SW620）中 Livin 的表达。我们发现对顺铂的不同反应与内源性Livin表达水平有关。在一组凋亡相关因子（p53、Bcl-2、Bcl-XL、BAX 和 survivin）中，Livin 的表达在顺铂治疗后以剂量依赖性方式上调。免疫细胞化学和核细胞质分级均表明顺铂处理后 Livin 仍保留在细胞质中。在试图探索其机制的过程中，我们发现 Livin 表达的升高并不是由于蛋白酶体降解的减少，而是在 mRNA 水平上增强。此外，顺铂治疗激活了哺乳动物雷帕霉素靶点 (mTOR) 通路，如 Akt1、mTOR、S6K 和 4E-BP1 磷酸化增加以及 Livin 升高所示。 PI3K 抑制剂 LY294002 抑制 mTOR 的磷酸化和 Livin 的上调。 Livin的稳定过表达抑制了caspase-3的激活，导致对顺铂产生耐药性，而siRNA敲除Livin则使结肠癌细胞对顺铂更加敏感。我们的研究与其他研究一起强调了 Livin 在结肠癌治疗中的潜力。
The antiapoptotic factor Livin has been considered critical for tumor progression and poor prognosis for variant types of tumors. However, there are only limited reports regarding its expression and biological functions in colon cancer. Here, we examined Livin expression in four colon cancer cell lines (HCT116, RKO, KM12C, and SW620) in the presence or absence of cisplatin that was used as a model reagent. We found the different response to cisplatin was related to endogenous Livin expression level. From among a panel of apoptosis-related factors (p53, Bcl-2, Bcl-XL, BAX, and survivin), the expression of Livin was upregulated after cisplatin treatment in a dose-dependent manner. Both immunocytochemistry and nuclear cytoplasmic fractionation indicated Livin remained in the cytoplasm after treatment with cisplatin. In an attempt to explore the mechanism, we found the elevated expression of Livin was not due to the decreased degradation by proteosome but was enhanced at the mRNA level. Besides, cisplatin treatment activated the mammalian target of rapamycin (mTOR) pathway as shown by increased phosphorylation of Akt1, mTOR, S6K, and 4E-BP1, together with the elevated Livin. The PI3K inhibitor LY294002 inhibited both the phosphorylation of mTOR and upregulation of Livin. The stable overexpression of Livin inhibited the activation of caspase-3 and led to resistance to cisplatin, while the knockdown of Livin by siRNA rendered colon cancer cells more sensitive to cisplatin. Our study, along with others, highlighted the potential of Livin for cancer therapy in colon cancer.