Src kinase inhibition restores E-cadherin expression in dasatinib-sensitive pancreatic cancer cells.
Src kinase inhibition restores E-cadherin expression in dasatinib-sensitive pancreatic cancer cells.
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DOI：
10.18632/oncotarget.26621
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发表时间：
2019-02-01
期刊：
影响因子：
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通讯作者：
Nagathihalli, Nagaraj S
中科院分区：
文献类型：
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作者：
Dosch, Austin R;Dai, Xizi;Nagathihalli, Nagaraj S
非受体酪氨酸激酶Src家族在胰腺导管腺癌（PDAC）中经常被激活，通过下调e -钙粘蛋白和诱导上皮-间质转化（EMT）促进疾病进展。本研究的目的是研究Src激酶抑制对恢复PDAC中E-cadherin水平的作用。人PDAC样本的免疫组织化学分析显示Src激活与E-cadherin水平呈负相关。在Src抑制剂达沙替尼（dasatinib， DST）治疗后，研究了PDAC细胞中E-cadherin的蛋白和mRNA水平、其各种转录抑制因子（Zeb1、Snail、Slug、lev -1、TWIST）的基因表达以及E-cadherin/ β -catenin亚细胞定位的变化。在药物敏感的PDAC细胞（BxPC3和SW1990）中，DST抑制了Slug mRNA的表达，促进了E-cadherin的转录，增加了E-cadherin/ β -catenin的总和膜水平，而在耐药的PANC1细胞中没有观察到变化。采用DST治疗BxPC3、PANC1和MiaPaCa-2异种侧腹肿瘤，观察其体内E-cadherin水平的变化。尽管DST在所有异种移植模型中抑制Src磷酸化，但E-cadherin水平仅在BxPC3异种移植肿瘤中恢复。这些结果表明，Src激酶抑制通过slug介导的E-cadherin抑制逆转药物敏感PDAC细胞中的EMT，并将E-cadherin确定为确定DST治疗反应的潜在生物标志物。
The Src family of non-receptor tyrosine kinases are frequently activated in pancreatic ductal adenocarcinoma (PDAC), contributing to disease progression through downregulation of E-cadherin and induction of epithelial-to-mesenchymal transition (EMT). The purpose of this study was to examine the efficacy of Src kinase inhibition in restoring E-cadherin levels in PDAC. Immunohistochemical analysis of human PDAC samples showed Src activation is inversely correlated with E-cadherin levels. Protein and mRNA levels of E-cadherin, the gene expression of its various transcriptional repressors (Zeb1, Snail, Slug, LEF-1, TWIST), and changes in sub-cellular localization of E-cadherin/beta-catenin in PDAC cells were characterized in response to treatment with the Src inhibitor, dasatinib (DST). DST repressed Slug mRNA expression, promoted E-cadherin transcription, and increased total and membranous E-cadherin/beta-catenin levels in drug-sensitive PDAC cells (BxPC3 and SW1990), however no change was observed in drug-resistant PANC1 cells. BxPC3, PANC1, and MiaPaCa-2 flank tumor xenografts were treated with DST to examine changes in E-cadherin levels in vivo. Although DST inhibited Src phosphorylation in all xenograft models, E-cadherin levels were only restored in BxPC3 xenograft tumors. These results suggest that Src kinase inhibition reverses EMT in drug-sensitive PDAC cells through Slug-mediated repression of E-cadherin and identifies E-cadherin as potential biomarker for determining response to DST treatment.