Cargando…

Suppression of STAT5b in pancreatic cancer cells leads to attenuated gemcitabine chemoresistance, adhesion and invasion

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies, and there is an urgent need for new therapeutic strategies based on the molecular biology of PDAC. Signal transducers and activators of transcription 5 (STAT5) are known to be activated in a variety of malignancies...

Descripción completa

Detalles Bibliográficos
Autores principales: SUMIYOSHI, HIROKI, MATSUSHITA, AKIRA, NAKAMURA, YOSHIHARU, MATSUDA, YOKO, ISHIWATA, TOSHIYUKI, NAITO, ZENYA, UCHIDA, EIJI
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869940/
https://www.ncbi.nlm.nih.gov/pubmed/27035235
http://dx.doi.org/10.3892/or.2016.4727
_version_ 1782432388852219904
author SUMIYOSHI, HIROKI
MATSUSHITA, AKIRA
NAKAMURA, YOSHIHARU
MATSUDA, YOKO
ISHIWATA, TOSHIYUKI
NAITO, ZENYA
UCHIDA, EIJI
author_facet SUMIYOSHI, HIROKI
MATSUSHITA, AKIRA
NAKAMURA, YOSHIHARU
MATSUDA, YOKO
ISHIWATA, TOSHIYUKI
NAITO, ZENYA
UCHIDA, EIJI
author_sort SUMIYOSHI, HIROKI
collection PubMed
description Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies, and there is an urgent need for new therapeutic strategies based on the molecular biology of PDAC. Signal transducers and activators of transcription 5 (STAT5) are known to be activated in a variety of malignancies and involved in tumor proliferation, apoptosis, and invasion, whereas the expression and biological role of STAT5b in PDAC are less clearly defined. In the present study, we examined the expression and role of STAT5b in human pancreatic cancer cell lines. Expressions of STAT5b mRNA and protein were detected in eight kinds of pancreatic cancer cells. Confocal microscopy and western blot analysis indicated that STAT5b is localized in both cytoplasm and nuclei. Immunoprecipitation analysis revealed tyrosine phosphorylation of STAT5b in pancreatic cancer cells. These results indicate that STAT5b in pancreatic cancer cells is constitutively activated. STAT5b shRNA clones in PANC-1 cells, which express relatively high levels of STAT5b, exhibited reduced chemoresistance against gemcitabine, adhesion and invasion compared to sham. On the other hand, AsPC-1 and BxPC3 cells, which express relatively low levels of STAT5b, exhibited reduced chemoresistance compared to PANC-1 cells. Moreover, STAT5b overexpression clones in AsPC-1 cells exhibited increased chemoresistance compared to sham. STAT5b shRNA clones in PANC-1 cells were more sensitive to the proapoptotic actions of gemcitabine, as evidenced by PARP and cleaved caspase-3 activation. Gemcitabine also significantly reduced Bcl-xL levels in the STAT5b shRNA-expressing cells. We also investigated the clinicopathological characteristics of STAT5b expression of PDAC. Although a significant correlation between STAT5b expression and overall survival rates was not observed, a significant correlation with main pancreatic duct invasion was observed. These findings suggest that STAT5b confers gemcitabine chemoresistance and promotes cell adherence and invasiveness in pancreatic cancer cells. Targeting STAT5b may lead to novel therapeutic strategies for PDAC.
format Online
Article
Text
id pubmed-4869940
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher D.A. Spandidos
record_format MEDLINE/PubMed
spelling pubmed-48699402016-05-20 Suppression of STAT5b in pancreatic cancer cells leads to attenuated gemcitabine chemoresistance, adhesion and invasion SUMIYOSHI, HIROKI MATSUSHITA, AKIRA NAKAMURA, YOSHIHARU MATSUDA, YOKO ISHIWATA, TOSHIYUKI NAITO, ZENYA UCHIDA, EIJI Oncol Rep Articles Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies, and there is an urgent need for new therapeutic strategies based on the molecular biology of PDAC. Signal transducers and activators of transcription 5 (STAT5) are known to be activated in a variety of malignancies and involved in tumor proliferation, apoptosis, and invasion, whereas the expression and biological role of STAT5b in PDAC are less clearly defined. In the present study, we examined the expression and role of STAT5b in human pancreatic cancer cell lines. Expressions of STAT5b mRNA and protein were detected in eight kinds of pancreatic cancer cells. Confocal microscopy and western blot analysis indicated that STAT5b is localized in both cytoplasm and nuclei. Immunoprecipitation analysis revealed tyrosine phosphorylation of STAT5b in pancreatic cancer cells. These results indicate that STAT5b in pancreatic cancer cells is constitutively activated. STAT5b shRNA clones in PANC-1 cells, which express relatively high levels of STAT5b, exhibited reduced chemoresistance against gemcitabine, adhesion and invasion compared to sham. On the other hand, AsPC-1 and BxPC3 cells, which express relatively low levels of STAT5b, exhibited reduced chemoresistance compared to PANC-1 cells. Moreover, STAT5b overexpression clones in AsPC-1 cells exhibited increased chemoresistance compared to sham. STAT5b shRNA clones in PANC-1 cells were more sensitive to the proapoptotic actions of gemcitabine, as evidenced by PARP and cleaved caspase-3 activation. Gemcitabine also significantly reduced Bcl-xL levels in the STAT5b shRNA-expressing cells. We also investigated the clinicopathological characteristics of STAT5b expression of PDAC. Although a significant correlation between STAT5b expression and overall survival rates was not observed, a significant correlation with main pancreatic duct invasion was observed. These findings suggest that STAT5b confers gemcitabine chemoresistance and promotes cell adherence and invasiveness in pancreatic cancer cells. Targeting STAT5b may lead to novel therapeutic strategies for PDAC. D.A. Spandidos 2016-06 2016-04-01 /pmc/articles/PMC4869940/ /pubmed/27035235 http://dx.doi.org/10.3892/or.2016.4727 Text en Copyright: © Sumiyoshi et al. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Articles
SUMIYOSHI, HIROKI
MATSUSHITA, AKIRA
NAKAMURA, YOSHIHARU
MATSUDA, YOKO
ISHIWATA, TOSHIYUKI
NAITO, ZENYA
UCHIDA, EIJI
Suppression of STAT5b in pancreatic cancer cells leads to attenuated gemcitabine chemoresistance, adhesion and invasion
title Suppression of STAT5b in pancreatic cancer cells leads to attenuated gemcitabine chemoresistance, adhesion and invasion
title_full Suppression of STAT5b in pancreatic cancer cells leads to attenuated gemcitabine chemoresistance, adhesion and invasion
title_fullStr Suppression of STAT5b in pancreatic cancer cells leads to attenuated gemcitabine chemoresistance, adhesion and invasion
title_full_unstemmed Suppression of STAT5b in pancreatic cancer cells leads to attenuated gemcitabine chemoresistance, adhesion and invasion
title_short Suppression of STAT5b in pancreatic cancer cells leads to attenuated gemcitabine chemoresistance, adhesion and invasion
title_sort suppression of stat5b in pancreatic cancer cells leads to attenuated gemcitabine chemoresistance, adhesion and invasion
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4869940/
https://www.ncbi.nlm.nih.gov/pubmed/27035235
http://dx.doi.org/10.3892/or.2016.4727
work_keys_str_mv AT sumiyoshihiroki suppressionofstat5binpancreaticcancercellsleadstoattenuatedgemcitabinechemoresistanceadhesionandinvasion
AT matsushitaakira suppressionofstat5binpancreaticcancercellsleadstoattenuatedgemcitabinechemoresistanceadhesionandinvasion
AT nakamurayoshiharu suppressionofstat5binpancreaticcancercellsleadstoattenuatedgemcitabinechemoresistanceadhesionandinvasion
AT matsudayoko suppressionofstat5binpancreaticcancercellsleadstoattenuatedgemcitabinechemoresistanceadhesionandinvasion
AT ishiwatatoshiyuki suppressionofstat5binpancreaticcancercellsleadstoattenuatedgemcitabinechemoresistanceadhesionandinvasion
AT naitozenya suppressionofstat5binpancreaticcancercellsleadstoattenuatedgemcitabinechemoresistanceadhesionandinvasion
AT uchidaeiji suppressionofstat5binpancreaticcancercellsleadstoattenuatedgemcitabinechemoresistanceadhesionandinvasion