Tankyrase 1 inhibitior XAV939 increases chemosensitivity in colon cancer cell lines via inhibition of the Wnt signaling pathway.
Tankyrase 1 inhibitior XAV939 increases chemosensitivity in colon cancer cell lines via inhibition of the Wnt signaling pathway.
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DOI：
10.3892/ijo.2016.3360
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发表时间：
2016-04
影响因子：
5.2
通讯作者：
Liu K
中科院分区：
文献类型：
--
作者：
Wu X;Luo F;Li J;Zhong X;Liu K
异常的Wnt信号通路与多种肿瘤类型相关，并在肿瘤干细胞（CSCs）的耐药性中起重要作用。为探讨WNT信号通路抑制剂XAV 939对结肠癌细胞耐药性的影响及其机制，采用5-氟尿嘧啶（5-FU）/顺铂（DDP）单独或联合XAV 939处理结肠癌细胞SW 480和SW 620。流式细胞仪检测细胞周期分布、凋亡水平及CD 133+细胞百分率。Western blotting检测Axin、β-catenin、EpCAM、TERT和DCAMKL-1的蛋白表达。XAV 939可上调SW 480和SW 620细胞中Axin的表达，减少β-catenin的表达。此外，XAV 939显著下调SW 480细胞中的CSC标志物EpCAM、TERT和DCAMKL-1，以及SW 620细胞中的EpCAM。XAV 939对SW 480和SW 620细胞的凋亡无明显影响，但对5-FU/DDP诱导的SW 480细胞凋亡有明显的促进作用，而对SW 620细胞的作用则不明显。总的来说，我们首次表明WNT信号通路抑制剂XAV 939能够显著增加5-FU/DDP诱导的结肠癌细胞凋亡，伴随着β-catenin，Axin和CSC标志物蛋白表达水平的改变。Axin是Wnt/β-catenin信号通路的重要组成部分，可能成为逆转结肠癌多药耐药的潜在分子靶点。
Aberrant Wnt signaling pathway is associated with a wide array of tumor types and plays an important role in the drug resistance of cancer stem cells (CSCs). To explore the effects and mechanism of WNT signaling pathway inhibitor XAV939 on drug resistance in colon cancer cells, the colon cancer cells SW480 and SW620 were treated with 5-fluorouracil (5-FU)/cisplatin (DDP) alone or combined with XAV939. Cell cycle distribution, apoptosis level and the percentage of CD133+ cells were detected by flow cytometry. The protein expression of Axin, β-catenin, EpCAM, TERT and DCAMKL-1 was detected by western blotting. XAV939 upregulated Axin, decreased the total and nuclei of β-catenin in SW480 and SW620 cells. Furthermore, XAV939 significantly downregulated the CSC markers EpCAM, TERT and DCAMKL-1 in SW480 cells, as well as EpCAM in SW620 cells. No significant difference was found in the apoptosis of SW480 and SW620 cells with XAV939 treatment, but XAV939 significantly increased apoptosis induced by 5-FU/DDP in SW480 cells, whereas, the effects were slight in SW620 cells. Collectively, we show for the first time that the WNT signaling pathway inhibitor XAV939 was able to significantly increase the apoptosis induced by 5-FU/DDP, accompanied by the protein expression level alternation of β-catenin, Axin and CSC markers in colon cancer cells. Axin, an important component of Wnt/β-catenin signaling pathway could be a potential molecular target for reversing multidrug resistance in colon cancer.