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

Content Provider	Europe PMC
Author	Dosch, Austin R. Dai, Xizi Gaidarski III, Alexander A. Shi, Chanjuan Castellanos, Jason A. VanSaun, Michael N. Merchant, Nipun B. Nagathihalli, Nagaraj S.
Copyright Year	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.
Journal	Oncotarget
Volume Number	10
PubMed Central reference number	PMC6383685
Issue Number	10
PubMed reference number	30800218
e-ISSN	19492553
DOI	10.18632/oncotarget.26621
Language	English
Publisher	Impact Journals LLC
Publisher Date	2019-02-01
Access Restriction	Open
Rights License	This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Copyright: © 2019 Dosch et al.
Subject Keyword	pancreatic ductal adenocarcinoma SRC kinase E-cadherin Dasatinib epithelial-to-mesenchymal transition (EMT)
Content Type	Text
Resource Type	Article
Subject	Oncology