Targeting CD133 reverses drug-resistance via the AKT/NF-κB/MDR1 pathway in colorectal cancer
Targeting CD133 reverses drug-resistance via the AKT/NF-κB/MDR1 pathway in colorectal cancer
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DOI：
10.1038/s41416-020-0783-0
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发表时间：
2020-03
影响因子：
8.8
通讯作者：
Zeting Yuan;Xin Liang;Y. Zhan;Ziyuan Wang;Jian Xu;Y. Qiu;Jie Wang;Yi-jun Cao;V. Le;H. Ly;Jianhua Xu;Wei Li;P. Yin;Ke Xu
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文献类型：
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作者：
Zeting Yuan;Xin Liang;Y. Zhan;Ziyuan Wang;Jian Xu;Y. Qiu;Jie Wang;Yi-jun Cao;V. Le;H. Ly;Jianhua Xu;Wei Li;P. Yin;Ke Xu
背景最近的研究表明，癌细胞的高干细胞性可能诱发多药耐药性。长期化疗后，结直肠癌中多药耐药蛋白1（MDR1）和CD133增加，但它们之间的关系尚不清楚。方法通过CCK-8测定、细胞凋亡测定、DOX摄取和保留、免疫组化、免疫荧光和流式细胞术测定结直肠癌中多药耐药和CSC特性之间的关系。使用 Spearman 等级统计检验和 Mann-Whitney 检验评估它们表达水平之间的相关性。此外，我们在体外和体内研究了CD133对AKT/NF-κB/MDR1信号通路抑制的作用。结果我们发现CD133随着耐药表型的出现而增加，并且通过患者样本的分析证明MDR1/P-gp的高表达始终伴随着CD133的阳性表达。 CD133 的上调或下调可以通过 CRC 中的 AKT/NF-κB/MDR1 信号传导调节 MDR。挽救实验表明，AKT/NF-κB信号通路是CD133调节CRC中MDR1/P-gp表达的主要机制。结论综上所述，我们的结果表明，靶向CD133可通过AKT/NF-κB/MDR1通路逆转耐药性，并且该通路可能作为逆转CRC中MDR的潜在治疗靶点。
BackgroundRecent studies have shown that multidrug resistance may be induced by the high stemness of cancer cells. Following prolonged chemotherapy, MDR protein 1 (MDR1) and CD133 increase in CRC, but the relationship between them is unclear.MethodsThe relationship between MDR and CSC properties in CRC was determined via CCK-8 assay, apoptosis assay, DOX uptake and retention, immunohistochemistry, immunofluorescence and flow cytometry. The correlations between their expression levels were evaluated using Spearman’s rank statistical test and the Mann-Whitney test. Furthermore, the effect of CD133 on the repression of the AKT/NF-κB/MDR1 signalling pathway was investigated in vitro and in vivo.ResultsWe found that CD133 increased with the emergence of drug-resistance phenotypes, and the high expression of MDR1/P-gp was consistently accompanied by positive expression of CD133 as demonstrated by the analysis of patient samples. Up- or downregulation of CD133 could regulate MDR via AKT/NF-κB/MDR1 signalling in CRC. A rescue experiment showed that the AKT/NF-κB signalling pathway is the main mechanism by which CD133 regulates MDR1/P-gp expression in CRC.ConclusionsTaken together, our results suggest that targeting CD133 reverses drug resistance via the AKT/NF-κB/MDR1 pathway and that this pathway might serve as a potential therapeutic target to reverse MDR in CRC.