Up-regulation of glycolysis promotes the stemness and EMT phenotypes in gemcitabine-resistant pancreatic cancer cells.
Up-regulation of glycolysis promotes the stemness and EMT phenotypes in gemcitabine-resistant pancreatic cancer cells.
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糖酵解上调促进吉西他滨耐药胰腺癌细胞的干性和 EMT 表型
DOI：
10.1111/jcmm.13126
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发表时间：
2017-09
影响因子：
5.3
通讯作者：
Yin T
中科院分区：
文献类型：
--
作者：
Zhao H;Duan Q;Zhang Z;Li H;Wu H;Shen Q;Wang C;Yin T
癌症干细胞（CSC）和上皮-间质转化（EMT）型细胞被认为是胰腺癌化疗耐药、肿瘤复发和转移的根本原因。我们的目的是描述的机制-特别是糖酵解-参与的CSC和EMT表型的调节。我们使用了吉西他滨耐药（GR）Patu 8988细胞系，该细胞系表现出明确的CSC和EMT表型，并显示出对糖酵解的依赖。使用2-脱氧-D-葡萄糖（2-DG）抑制糖酵解显著增强了吉西他滨的细胞毒性，并在体外和体内抑制了GR细胞中的CSC和EMT表型。有趣的是，使用活性氧（ROS）清除剂N-乙酰半胱氨酸（NAC）恢复了CSC和EMT表型。H2 O2产生类似于2-DG的变化，表明ROS参与GR细胞的获得性癌症干细胞性和EMT表型。此外，胰腺CSC标志物双皮质素样激酶1（DCLK 1）在GR细胞中高度表达并调节干细胞和EMT表型。2-DG和H2 O2处理均抑制DCLK 1表达，NAC也可挽救DCLK 1表达。总之，这些发现揭示了糖酵解促进DCLK 1的表达，并通过维持化疗耐药GR细胞中的低ROS水平来维持CSC和EMT表型。糖酵解-ROS-DCLK 1通路可能是逆转胰腺癌恶性行为的潜在靶点。
Cancer stem cells (CSCs) and epithelial–mesenchymal transition (EMT)‐type cells are considered as underlying causes of chemoresistance, tumour recurrence and metastasis in pancreatic cancer. We aimed to describe the mechanisms – particularly glycolysis – involved in the regulation of the CSC and EMT phenotypes. We used a gemcitabine‐resistant (GR) Patu8988 cell line, which exhibited clear CSC and EMT phenotypes and showed reliance on glycolysis. Inhibition of glycolysis using 2‐deoxy‐D‐glucose (2‐DG) significantly enhanced the cytotoxicity of gemcitabine and inhibited the CSC and EMT phenotypes in GR cells both in vitro and in vivo. Intriguingly, the use of the reactive oxygen species (ROS) scavenger N‐acetylcysteine (NAC) restored the CSC and EMT phenotypes. H2O2 produced changes similar to those of 2‐DG, indicating that ROS were involved in the acquired cancer stemness and EMT phenotypes of GR cells. Moreover, doublecortin‐like kinase 1 (DCLK1), a pancreatic CSC marker, was highly expressed and regulated the stemness and EMT phenotypes in GR cell. Both 2‐DG and H2O2 treatment suppressed DCLK1 expression, which was also rescued by NAC. Together, these findings revealed that glycolysis promotes the expression of DCLK1 and maintains the CSC and EMT phenotypes via maintenance of low ROS levels in chemoresistant GR cells. The glycolysis‐ROS‐DCLK1 pathway may be potential targets for reversing the malignant behaviour of pancreatic cancer.
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影响因子：
3.7
作者：
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通讯作者：
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