Src kinase inhibition restores E-cadherin expression in Dasatinib-sensitive pancreatic cancer cells

Austin R. Dosch, Xizi Dai, Alexander A. Gaidarski, Chanjuan Shi, Jason A. Castellanos, Michael N. VanSaun, Nipun B. Merchant, Nagaraj S. Nagathihalli

Research output: Contribution to journalArticle

Abstract

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/β-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/β-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.

Original languageEnglish (US)
Pages (from-to)1056-1069
Number of pages14
JournalOncotarget
Volume10
Issue number10
DOIs
StatePublished - Feb 1 2019

Keywords

  • Dasatinib
  • E-cadherin
  • Epithelial-to-mesenchymal transition (EMT)
  • Pancreatic ductal adenocarcinoma
  • SRC kinase

ASJC Scopus subject areas

  • Oncology

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