Oncotarget

Research Papers:

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

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

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Oncotarget. 2019; 10:1056-1069. https://doi.org/10.18632/oncotarget.26621

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Abstract

Austin R. Dosch1,2, Xizi Dai1,2, Alexander A. Gaidarski III1,2, Chanjuan Shi3, Jason A. Castellanos4, Michael N. VanSaun1,2, Nipun B. Merchant1,2 and Nagaraj S. Nagathihalli1,2

1Division of Surgical Oncology, Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA

2Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL, USA

3Department of Pathology, Vanderbilt University School of Medicine, Nashville, TN, USA

4Department of Surgery, Vanderbilt University School of Medicine, Nashville, TN, USA

Correspondence to:

Nagaraj S. Nagathihalli, email: nnagathihalli@med.miami.edu

Keywords: pancreatic ductal adenocarcinoma; SRC kinase; E-cadherin; Dasatinib; epithelial-to-mesenchymal transition (EMT)

Received: October 18, 2018    Accepted: January 02, 2019    Published: February 01, 2019

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.


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