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 N.
AU - Merchant, Nipun B.
AU - Nagathihalli, Nagaraj S.
N1 - Funding Information:
This work was supported by the NIH NCI R21 CA209536, American Cancer Society IRG 98-277-13 and Stanley Glaser Foundation Research Award (UM SJG 2017-24) to N.S. Nagathihalli, R01CA231052 to M.N. VanSaun, and R01 CA161976 and NIH T32 CA211034 to N.B. Merchant. Histopathology Core Service was performed through the Sylvester Comprehensive Cancer Center (SCCC) support grant (N.B. Merchant and N.S. Nagathihalli).
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
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U2 - 10.18632/oncotarget.26621
DO - 10.18632/oncotarget.26621
M3 - Article
AN - SCOPUS:85061036159
VL - 10
SP - 1056
EP - 1069
JO - Oncotarget
JF - Oncotarget
SN - 1949-2553
IS - 10
ER -