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 language | English (US) |
|---|---|
| Pages (from-to) | 1056-1069 |
| Number of pages | 14 |
| Journal | Oncotarget |
| Volume | 10 |
| Issue number | 10 |
| State | Published - Feb 1 2019 |
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Keywords
- Dasatinib
- E-cadherin
- Epithelial-to-mesenchymal transition (EMT)
- Pancreatic ductal adenocarcinoma
- SRC kinase
ASJC Scopus subject areas
- Oncology
Cite this
Src kinase inhibition restores E-cadherin expression in Dasatinib-sensitive pancreatic cancer cells. / Dosch, Austin R.; Dai, Xizi; Gaidarski, Alexander A.; Shi, Chanjuan; Castellanos, Jason A.; Vansaun, Michael; Merchant, Nipun; Nagathihalli, Nagaraj.
In: Oncotarget, Vol. 10, No. 10, 01.02.2019, p. 1056-1069.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Src kinase inhibition restores E-cadherin expression in Dasatinib-sensitive pancreatic cancer cells
AU - Dosch, Austin R.
AU - Dai, Xizi
AU - Gaidarski, Alexander A.
AU - Shi, Chanjuan
AU - Castellanos, Jason A.
AU - Vansaun, Michael
AU - Merchant, Nipun
AU - Nagathihalli, Nagaraj
PY - 2019/2/1
Y1 - 2019/2/1
N2 - 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.
AB - 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.
KW - Dasatinib
KW - E-cadherin
KW - Epithelial-to-mesenchymal transition (EMT)
KW - Pancreatic ductal adenocarcinoma
KW - SRC kinase
UR - http://www.scopus.com/inward/record.url?scp=85061036159&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85061036159&partnerID=8YFLogxK
M3 - Article
AN - SCOPUS:85061036159
VL - 10
SP - 1056
EP - 1069
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 10
ER -