P21-activated kinase 1 (Pak1) signaling influences therapeutic outcome in pancreatic cancer

Therapeutic resistance to gemcitabine in pancreatic ductal adenocarcinoma (PDAC) is attributed to various cellular mechanisms and signaling molecules that influence as a single factor or in combination. In this study, utilizing in vitro p21-activated kinase 1 (Pak1) overexpression and knockdown cell...

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Veröffentlicht in:Annals of oncology 2016-08, Vol.27 (8), p.1546-1556
Hauptverfasser: Jagadeeshan, S., Subramanian, A., Tentu, S., Beesetti, S., Singhal, M., Raghavan, S., Surabhi, R.P., Mavuluri, J., Bhoopalan, H., Biswal, J., Pitani, R.S., Chidambaram, S., Sundaram, S., Malathi, R., Jeyaraman, J., Nair, A.S., Venkatraman, G., Rayala, S.K.
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container_end_page 1556
container_issue 8
container_start_page 1546
container_title Annals of oncology
container_volume 27
creator Jagadeeshan, S.
Subramanian, A.
Tentu, S.
Beesetti, S.
Singhal, M.
Raghavan, S.
Surabhi, R.P.
Mavuluri, J.
Bhoopalan, H.
Biswal, J.
Pitani, R.S.
Chidambaram, S.
Sundaram, S.
Malathi, R.
Jeyaraman, J.
Nair, A.S.
Venkatraman, G.
Rayala, S.K.
description Therapeutic resistance to gemcitabine in pancreatic ductal adenocarcinoma (PDAC) is attributed to various cellular mechanisms and signaling molecules that influence as a single factor or in combination. In this study, utilizing in vitro p21-activated kinase 1 (Pak1) overexpression and knockdown cell line models along with in vivo athymic mouse tumor xenograft models and clinical samples, we demonstrate that Pak1 is a crucial signaling kinase in gemcitabine resistance. Pak1 kindles resistance via modulation of epithelial–mesenchymal transition and activation of pancreatic stellate cells. Our results from gemcitabine-resistant and -sensitive cell line models showed that elevated Pak1 kinase activity is required to confer gemcitabine resistance. This was substantiated by elevated levels of phosphorylated Pak1 and ribonucleotide reductase M1 levels in the majority of human PDAC tumors when compared with normal. Delineation of the signaling pathway revealed that Pak1 confers resistance to gemcitabine by preventing DNA damage, inhibiting apoptosis and regulating survival signals via NF-κB. Furthermore, we found that Pak1 is an upstream interacting substrate of transforming growth factor β-activated kinase 1—a molecule implicated in gemcitabine resistance. Molecular mechanistic studies revealed that gemcitabine docks with the active site of Pak1; furthermore, gemcitabine treatment induces Pak1 kinase activity both in vivo and in cell-free system. Finally, results from athymic mouse tumor models illustrated that Pak1 inhibition by IPA-3 enhances the cytotoxicity of gemcitabine and brings about pancreatic tumor regression. To our knowledge, this is the first study illustrating the mechanistic role of Pak1 in causing gemcitabine resistance via multiple signaling crosstalks, and hence Pak1-specific inhibitors will prove to be a better adjuvant with existing chemotherapy modality for PDAC.
doi_str_mv 10.1093/annonc/mdw184
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In this study, utilizing in vitro p21-activated kinase 1 (Pak1) overexpression and knockdown cell line models along with in vivo athymic mouse tumor xenograft models and clinical samples, we demonstrate that Pak1 is a crucial signaling kinase in gemcitabine resistance. Pak1 kindles resistance via modulation of epithelial–mesenchymal transition and activation of pancreatic stellate cells. Our results from gemcitabine-resistant and -sensitive cell line models showed that elevated Pak1 kinase activity is required to confer gemcitabine resistance. This was substantiated by elevated levels of phosphorylated Pak1 and ribonucleotide reductase M1 levels in the majority of human PDAC tumors when compared with normal. Delineation of the signaling pathway revealed that Pak1 confers resistance to gemcitabine by preventing DNA damage, inhibiting apoptosis and regulating survival signals via NF-κB. Furthermore, we found that Pak1 is an upstream interacting substrate of transforming growth factor β-activated kinase 1—a molecule implicated in gemcitabine resistance. Molecular mechanistic studies revealed that gemcitabine docks with the active site of Pak1; furthermore, gemcitabine treatment induces Pak1 kinase activity both in vivo and in cell-free system. Finally, results from athymic mouse tumor models illustrated that Pak1 inhibition by IPA-3 enhances the cytotoxicity of gemcitabine and brings about pancreatic tumor regression. 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Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. 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Furthermore, we found that Pak1 is an upstream interacting substrate of transforming growth factor β-activated kinase 1—a molecule implicated in gemcitabine resistance. Molecular mechanistic studies revealed that gemcitabine docks with the active site of Pak1; furthermore, gemcitabine treatment induces Pak1 kinase activity both in vivo and in cell-free system. Finally, results from athymic mouse tumor models illustrated that Pak1 inhibition by IPA-3 enhances the cytotoxicity of gemcitabine and brings about pancreatic tumor regression. 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In this study, utilizing in vitro p21-activated kinase 1 (Pak1) overexpression and knockdown cell line models along with in vivo athymic mouse tumor xenograft models and clinical samples, we demonstrate that Pak1 is a crucial signaling kinase in gemcitabine resistance. Pak1 kindles resistance via modulation of epithelial–mesenchymal transition and activation of pancreatic stellate cells. Our results from gemcitabine-resistant and -sensitive cell line models showed that elevated Pak1 kinase activity is required to confer gemcitabine resistance. This was substantiated by elevated levels of phosphorylated Pak1 and ribonucleotide reductase M1 levels in the majority of human PDAC tumors when compared with normal. Delineation of the signaling pathway revealed that Pak1 confers resistance to gemcitabine by preventing DNA damage, inhibiting apoptosis and regulating survival signals via NF-κB. Furthermore, we found that Pak1 is an upstream interacting substrate of transforming growth factor β-activated kinase 1—a molecule implicated in gemcitabine resistance. Molecular mechanistic studies revealed that gemcitabine docks with the active site of Pak1; furthermore, gemcitabine treatment induces Pak1 kinase activity both in vivo and in cell-free system. Finally, results from athymic mouse tumor models illustrated that Pak1 inhibition by IPA-3 enhances the cytotoxicity of gemcitabine and brings about pancreatic tumor regression. To our knowledge, this is the first study illustrating the mechanistic role of Pak1 in causing gemcitabine resistance via multiple signaling crosstalks, and hence Pak1-specific inhibitors will prove to be a better adjuvant with existing chemotherapy modality for PDAC.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>27117533</pmid><doi>10.1093/annonc/mdw184</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record>
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subjects Adenocarcinoma - drug therapy
Adenocarcinoma - genetics
Adenocarcinoma - pathology
Animals
Carcinoma, Pancreatic Ductal - drug therapy
Carcinoma, Pancreatic Ductal - genetics
Carcinoma, Pancreatic Ductal - pathology
Cell Line, Tumor
Deoxycytidine - administration & dosage
Deoxycytidine - adverse effects
Deoxycytidine - analogs & derivatives
desmoplastic
DNA Damage - drug effects
Drug Resistance, Neoplasm - genetics
Epithelial-Mesenchymal Transition - drug effects
gemcitabine
Gene Expression Regulation, Neoplastic - drug effects
Humans
IPA-3
Mice
p21-Activated Kinases - genetics
PAK1
Pancreatic Stellate Cells - drug effects
Pancreatic Stellate Cells - pathology
resistance
Xenograft Model Antitumor Assays
title P21-activated kinase 1 (Pak1) signaling influences therapeutic outcome in pancreatic cancer
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