Translationally controlled tumour protein TCTP is induced early in human colorectal tumours and contributes to the resistance of HCT116 colon cancer cells to 5-FU and oxaliplatin.
Translationally controlled tumour protein TCTP is induced early in human colorectal tumours and contributes to the resistance of HCT116 colon cancer cells to 5-FU and oxaliplatin.
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DOI：
10.1186/s12964-017-0164-3
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发表时间：
2017-02-01
期刊：
影响因子：
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通讯作者：
Aghmesheh M
中科院分区：
文献类型：
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作者：
Bommer UA;Vine KL;Puri P;Engel M;Belfiore L;Fildes K;Batterham M;Lochhead A;Aghmesheh M
翻译控制的肿瘤蛋白TCTP是一种抗凋亡蛋白，经常在癌症中过表达，其中高水平通常与患者预后不良相关。TCTP可能参与保护癌细胞免受抗癌药物的细胞毒性作用。在这里，我们研究了TCTP水平在人类结直肠癌（CRC）的早期增加和HCT 116结肠癌细胞中TCTP表达的调节，以响应抗癌药物5-FU和奥沙利铂的治疗。使用免疫组化，我们评估TCTP水平的手术样本从腺瘤和腺癌的结肠，相比正常的结肠组织。我们还研究了TCTP在HCT 116结肠癌细胞中对5-FU和奥沙利铂反应的调节。通过RT-qPCR评估TCTP mRNA水平。我们使用mTOR激酶抑制剂来证明在这些条件下TCTP的mTOR依赖性翻译调节。利用实时细胞分析系统（RTCA）和MTS检测技术，研究了TCTP基因敲减对HCT 116细胞对抗癌药物5-FU和奥沙利铂敏感性的影响。1.与正常结肠组织相比，TCTP水平在结肠腺瘤和腺癌中显著增加。2.在HCT 116结肠癌细胞中，TCTP蛋白水平响应于5-FU和奥沙利铂处理而上调约4倍，而TCTP mRNA水平下调。3. mTOR激酶抑制剂阻止了TCTP蛋白的上调，表明在这些条件下TCTP通过mTOR复合物1信号传导途径被间接调节。4.使用两种细胞测定系统，我们证明了TCTP敲低使HCT 116细胞对5-FU和奥沙利铂引起的细胞毒性敏感。我们的研究结果表明，TCTP水平在CRC发展的早期阶段显着增加。在结肠癌细胞中，这种蛋白质的表达在用DNA损伤性抗癌药物5-FU和奥沙利铂治疗期间大幅上调，作为细胞应激反应的一部分。因此，TCTP可能有助于抗癌药物耐药性的发展。这些发现表明TCTP可能适合作为生物标志物，并且使用5-FU/奥沙利铂与mTOR激酶抑制剂的组合治疗可能是预防对这些药物产生耐药性的途径。本文的在线版本（doi：10.1186/s12964-017-0164-3）包含补充材料，可供授权用户使用。
Translationally controlled tumour protein TCTP is an anti-apoptotic protein frequently overexpressed in cancers, where high levels are often associated with poor patient outcome. TCTP may be involved in protecting cancer cells against the cytotoxic action of anti-cancer drugs. Here we study the early increase of TCTP levels in human colorectal cancer (CRC) and the regulation of TCTP expression in HCT116 colon cancer cells, in response to treatment with the anti-cancer drugs 5-FU and oxaliplatin. Using immunohistochemistry, we assessed TCTP levels in surgical samples from adenomas and adenocarcinomas of the colon, compared to normal colon tissue. We also studied the regulation of TCTP in HCT116 colon cancer cells in response to 5-FU and oxaliplatin by western blotting. TCTP mRNA levels were assessed by RT-qPCR. We used mTOR kinase inhibitors to demonstrate mTOR-dependent translational regulation of TCTP under these conditions. Employing the Real-Time Cell Analysis (RTCA) System and the MTS assay, we investigated the effect of TCTP-knockdown on the sensitivity of HCT116 cells to the anti-cancer drugs 5-FU and oxaliplatin. 1. TCTP levels are significantly increased in colon adenomas and adenocarcinomas, compared to normal colon tissue. 2. TCTP protein levels are about 4-fold upregulated in HCT116 colon cancer cells, in response to 5-FU and oxaliplatin treatment, whereas TCTP mRNA levels are down regulated. 3. mTOR kinase inhibitors prevented the up-regulation of TCTP protein, indicating that TCTP is translationally regulated through the mTOR complex 1 signalling pathway under these conditions. 4. Using two cellular assay systems, we demonstrated that TCTP-knockdown sensitises HCT116 cells to the cytotoxicity caused by 5-FU and oxaliplatin. Our results demonstrate that TCTP levels increase significantly in the early stages of CRC development. In colon cancer cells, expression of this protein is largely upregulated during treatment with the DNA-damaging anti-cancer drugs 5-FU and oxaliplatin, as part of the cellular stress response. TCTP may thus contribute to the development of anti-cancer drug resistance. These findings indicate that TCTP might be suitable as a biomarker and that combinatorial treatment using 5-FU/oxaliplatin, together with mTOR kinase inhibitors, could be a route to preventing the development of resistance to these drugs. The online version of this article (doi:10.1186/s12964-017-0164-3) contains supplementary material, which is available to authorized users.