Proteasome inhibitor MG132 induces thyroid cancer cell apoptosis by modulating the activity of transcription factor FOXO3a
Proteasome inhibitor MG132 induces thyroid cancer cell apoptosis by modulating the activity of transcription factor FOXO3a
复制标题
蛋白酶体抑制剂MG132通过调节转录因子FOXO3a的活性诱导甲状腺癌细胞凋亡
DOI：
10.1007/s12020-017-1256-y
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发表时间：
2017-04-01
期刊：
影响因子：
3.7
通讯作者：
Hou，Peng
中科院分区：
文献类型：
--
作者：
Qiang，Wei;Sui，Fang;Hou，Peng
蛋白酶体抑制剂是一种很有前途的抗肿瘤药物，在恶性细胞中具有较好的细胞毒性，并已在多种血液系统恶性肿瘤中显示出临床疗效。P53依赖的细胞凋亡已被报道为一种主要的机制。然而，在突变型p53的癌细胞中也可以发现凋亡，提示P53非依赖的机制参与了这一过程。肿瘤抑制因子Forkhead Box 03是蛋白酶体降解的另一种底物，它也通过诱导细胞凋亡发挥部分作用。本研究旨在探讨蛋白酶体抑制对甲状腺癌细胞叉头盒O_3表达和活性的影响。采用流式细胞术、免疫印迹、免疫荧光染色和定量RT-PCR等方法，检测蛋白酶体抑制剂MG132诱导的甲状腺癌细胞凋亡及其对叉头盒O_3表达和活性的影响。结果表明，MG132可诱导P53野生型和突变型甲状腺癌细胞发生明显的凋亡，并导致P53蛋白积聚，而P53的促凋亡靶点仅在野生型P53细胞中转录上调。值得注意的是，经MG132处理后，无论P53基因状态如何，转录因子叉头盒O_3在甲状腺癌细胞中的积聚和核转位及其促凋亡靶基因的转录上调。异位过表达可促进细胞凋亡，而沉默叉头盒O_3则可抑制细胞凋亡。总之，我们证明了蛋白酶体抑制剂MG132至少部分地通过调节叉头盒O_3的活性来诱导甲状腺癌细胞的凋亡。
Proteasome inhibitors are promising antitumor drugs with preferable cytotoxicity in malignant cells and have exhibited clinical efficiency in several hematologic malignancies. P53-dependent apoptosis has been reported to be a major mechanism underlying. However, apoptosis can also be found in cancer cells with mutant-type p53, suggesting the involvement of p53-independent mechanism. Tumor suppressor forkhead Box O3 is another substrate of proteasomal degradation, which also functions partially through inducing apoptosis. The aim of this study was to explore the effect of proteasome inhibition on the expression and activity of forkhead Box O3 in thyroid cancer cells. Using flow cytometry, western blot, immunofluorescence staining and quantitative RT-PCR assays, we assessed proteasome inhibitor MG132-induced apoptosis in thyroid cancer cells and its effect on the expression and activity of forkhead Box O3. The resulted showed that MG132 induced significant apoptosis, and caused the accumulation of p53 protein in both p53 wild-type and mutant-type thyroid cancer cell lines, whereas the proapoptotic targets of p53 were transcriptionally upregulated only in the p53 wild-type cells. Strikingly, upon MG132 administration, the accumulation and nuclear translocation of transcription factor forkhead Box O3 as well as transcriptional upregulation of its proapoptotic target genes were found in thyroid cancer cells regardless of p53 status. Cell apoptosis was enhanced by ectopic overexpression while attenuated by silencing of forkhead Box O3. Altogether, we demonstrated that proteasome inhibitor MG132 induces thyroid cancer cell apoptosis at least partially through modulating forkhead Box O3 activity.