Cargando…

Protein Kinase C Zeta Regulates Human Pancreatic Cancer Cell Transformed Growth and Invasion through a STAT3-Dependent Mechanism

Pancreatic cancer is a very aggressive disease with few therapeutic options. In this study, we investigate the role of protein kinase C zeta (PKCζ) in pancreatic cancer cells. PKCζ has been shown to act as either a tumor suppressor or tumor promoter depending upon the cellular context. We find that...

Descripción completa

Detalles Bibliográficos
Autores principales: Butler, Amanda M., Scotti Buzhardt, Michele L., Li, Shuhua, Smith, Kristin E., Fields, Alan P., Murray, Nicole R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756013/
https://www.ncbi.nlm.nih.gov/pubmed/24015205
http://dx.doi.org/10.1371/journal.pone.0072061
_version_ 1782282021346738176
author Butler, Amanda M.
Scotti Buzhardt, Michele L.
Li, Shuhua
Smith, Kristin E.
Fields, Alan P.
Murray, Nicole R.
author_facet Butler, Amanda M.
Scotti Buzhardt, Michele L.
Li, Shuhua
Smith, Kristin E.
Fields, Alan P.
Murray, Nicole R.
author_sort Butler, Amanda M.
collection PubMed
description Pancreatic cancer is a very aggressive disease with few therapeutic options. In this study, we investigate the role of protein kinase C zeta (PKCζ) in pancreatic cancer cells. PKCζ has been shown to act as either a tumor suppressor or tumor promoter depending upon the cellular context. We find that PKCζ expression is either maintained or elevated in primary human pancreatic tumors, but is never lost, consistent with PKCζ playing a promotive role in the pancreatic cancer phenotype. Genetic inhibition of PKCζ reduced adherent growth, cell survival and anchorage-independent growth of human pancreatic cancer cells in vitro. Furthermore, PKCζ inhibition reduced orthotopic tumor size in vivo by inhibiting tumor cell proliferation and increasing tumor necrosis. In addition, PKCζ inhibition reduced tumor metastases in vivo, and caused a corresponding reduction in pancreatic cancer cell invasion in vitro. Signal transducer and activator of transcription 3 (STAT3) is often constitutively active in pancreatic cancer, and plays an important role in pancreatic cancer cell survival and metastasis. Interestingly, inhibition of PKCζ significantly reduced constitutive STAT3 activation in pancreatic cancer cells in vitro and in vivo. Pharmacologic inhibition of STAT3 mimicked the phenotype of PKCζ inhibition, and expression of a constitutively active STAT3 construct rescued the transformed phenotype in PKCζ-deficient cells. We conclude that PKCζ is required for pancreatic cancer cell transformed growth and invasion in vitro and tumorigenesis in vivo, and that STAT3 is an important downstream mediator of the pro-carcinogenic effects of PKCζ in pancreatic cancer cells.
format Online
Article
Text
id pubmed-3756013
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-37560132013-09-06 Protein Kinase C Zeta Regulates Human Pancreatic Cancer Cell Transformed Growth and Invasion through a STAT3-Dependent Mechanism Butler, Amanda M. Scotti Buzhardt, Michele L. Li, Shuhua Smith, Kristin E. Fields, Alan P. Murray, Nicole R. PLoS One Research Article Pancreatic cancer is a very aggressive disease with few therapeutic options. In this study, we investigate the role of protein kinase C zeta (PKCζ) in pancreatic cancer cells. PKCζ has been shown to act as either a tumor suppressor or tumor promoter depending upon the cellular context. We find that PKCζ expression is either maintained or elevated in primary human pancreatic tumors, but is never lost, consistent with PKCζ playing a promotive role in the pancreatic cancer phenotype. Genetic inhibition of PKCζ reduced adherent growth, cell survival and anchorage-independent growth of human pancreatic cancer cells in vitro. Furthermore, PKCζ inhibition reduced orthotopic tumor size in vivo by inhibiting tumor cell proliferation and increasing tumor necrosis. In addition, PKCζ inhibition reduced tumor metastases in vivo, and caused a corresponding reduction in pancreatic cancer cell invasion in vitro. Signal transducer and activator of transcription 3 (STAT3) is often constitutively active in pancreatic cancer, and plays an important role in pancreatic cancer cell survival and metastasis. Interestingly, inhibition of PKCζ significantly reduced constitutive STAT3 activation in pancreatic cancer cells in vitro and in vivo. Pharmacologic inhibition of STAT3 mimicked the phenotype of PKCζ inhibition, and expression of a constitutively active STAT3 construct rescued the transformed phenotype in PKCζ-deficient cells. We conclude that PKCζ is required for pancreatic cancer cell transformed growth and invasion in vitro and tumorigenesis in vivo, and that STAT3 is an important downstream mediator of the pro-carcinogenic effects of PKCζ in pancreatic cancer cells. Public Library of Science 2013-08-28 /pmc/articles/PMC3756013/ /pubmed/24015205 http://dx.doi.org/10.1371/journal.pone.0072061 Text en © 2013 Butler et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Butler, Amanda M.
Scotti Buzhardt, Michele L.
Li, Shuhua
Smith, Kristin E.
Fields, Alan P.
Murray, Nicole R.
Protein Kinase C Zeta Regulates Human Pancreatic Cancer Cell Transformed Growth and Invasion through a STAT3-Dependent Mechanism
title Protein Kinase C Zeta Regulates Human Pancreatic Cancer Cell Transformed Growth and Invasion through a STAT3-Dependent Mechanism
title_full Protein Kinase C Zeta Regulates Human Pancreatic Cancer Cell Transformed Growth and Invasion through a STAT3-Dependent Mechanism
title_fullStr Protein Kinase C Zeta Regulates Human Pancreatic Cancer Cell Transformed Growth and Invasion through a STAT3-Dependent Mechanism
title_full_unstemmed Protein Kinase C Zeta Regulates Human Pancreatic Cancer Cell Transformed Growth and Invasion through a STAT3-Dependent Mechanism
title_short Protein Kinase C Zeta Regulates Human Pancreatic Cancer Cell Transformed Growth and Invasion through a STAT3-Dependent Mechanism
title_sort protein kinase c zeta regulates human pancreatic cancer cell transformed growth and invasion through a stat3-dependent mechanism
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756013/
https://www.ncbi.nlm.nih.gov/pubmed/24015205
http://dx.doi.org/10.1371/journal.pone.0072061
work_keys_str_mv AT butleramandam proteinkinaseczetaregulateshumanpancreaticcancercelltransformedgrowthandinvasionthroughastat3dependentmechanism
AT scottibuzhardtmichelel proteinkinaseczetaregulateshumanpancreaticcancercelltransformedgrowthandinvasionthroughastat3dependentmechanism
AT lishuhua proteinkinaseczetaregulateshumanpancreaticcancercelltransformedgrowthandinvasionthroughastat3dependentmechanism
AT smithkristine proteinkinaseczetaregulateshumanpancreaticcancercelltransformedgrowthandinvasionthroughastat3dependentmechanism
AT fieldsalanp proteinkinaseczetaregulateshumanpancreaticcancercelltransformedgrowthandinvasionthroughastat3dependentmechanism
AT murraynicoler proteinkinaseczetaregulateshumanpancreaticcancercelltransformedgrowthandinvasionthroughastat3dependentmechanism