Cargando…

Targeting PKCι-PAK1 signaling pathways in EGFR and KRAS mutant adenocarcinoma and lung squamous cell carcinoma

INTRODUCTION: p21-activated kinase 1 (PAK1) stimulates growth and metastasis in non-small cell lung cancer (NSCLC). Protein kinase C iota (PKCι) is an enzyme highly expressed in NSCLC, regulating PAK1 signaling. In the present study we explored whether the PKCι-PAK1 signaling pathway approach can be...

Descripción completa

Detalles Bibliográficos
Autores principales: Ito, Masaoki, Codony-Servat, Carles, Codony-Servat, Jordi, Lligé, David, Chaib, Imane, Sun, Xiaoyan, Miao, Jing, Sun, Rongwei, Cai, Xueting, Verlicchi, Alberto, Okada, Morihito, Molina-Vila, Miguel Angel, Karachaliou, Niki, Cao, Peng, Rosell, Rafael
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819333/
https://www.ncbi.nlm.nih.gov/pubmed/31660987
http://dx.doi.org/10.1186/s12964-019-0446-z
_version_ 1783463704420941824
author Ito, Masaoki
Codony-Servat, Carles
Codony-Servat, Jordi
Lligé, David
Chaib, Imane
Sun, Xiaoyan
Miao, Jing
Sun, Rongwei
Cai, Xueting
Verlicchi, Alberto
Okada, Morihito
Molina-Vila, Miguel Angel
Karachaliou, Niki
Cao, Peng
Rosell, Rafael
author_facet Ito, Masaoki
Codony-Servat, Carles
Codony-Servat, Jordi
Lligé, David
Chaib, Imane
Sun, Xiaoyan
Miao, Jing
Sun, Rongwei
Cai, Xueting
Verlicchi, Alberto
Okada, Morihito
Molina-Vila, Miguel Angel
Karachaliou, Niki
Cao, Peng
Rosell, Rafael
author_sort Ito, Masaoki
collection PubMed
description INTRODUCTION: p21-activated kinase 1 (PAK1) stimulates growth and metastasis in non-small cell lung cancer (NSCLC). Protein kinase C iota (PKCι) is an enzyme highly expressed in NSCLC, regulating PAK1 signaling. In the present study we explored whether the PKCι-PAK1 signaling pathway approach can be an efficient target in different types of NSCLC cell and mouse models. METHODS: The effect of IPA-3 (PAK1 inhibitor) plus auranofin (PKCι inhibitor) combination was evaluated by cell viability assay, colony formation and western blotting assay, using three types of NSCLC cell lines: EGFR or KRAS mutant adenocarcinoma and squamous cell carcinoma with PAK1 amplification. In addition, for clinical availability, screening for new PAK1 inhibitors was carried out and the compound OTSSP167 was evaluated in combination with auranofin in cell and mice models. RESULTS: The combination of IPA-3 or OTSSP167 plus auranofin showed high synergism for inhibiting cell viability and colony formation in three cell lines. Mechanistic characterization revealed that this drug combination abrogated expression and activation of membrane receptors and downstream signaling proteins crucial in lung cancer: EGFR, MET, PAK1, PKCι, ERK1/2, AKT, YAP1 and mTOR. A nude mouse xenograft assay demonstrated that this drug combination strongly suppressed tumor volume compared with single drug treatment. CONCLUSIONS: Combination of IPA-3 or OTSSP167 and auranofin was highly synergistic in EGFR or KRAS mutant adenocarcinoma and squamous cell carcinoma cell lines and decreased tumor volume in mice models. It is of interest to further test the targeting of PKCι-PAK1 signaling pathways in EGFR mutant, KRAS mutant and squamous NSCLC patients.
format Online
Article
Text
id pubmed-6819333
institution National Center for Biotechnology Information
language English
publishDate 2019
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-68193332019-10-31 Targeting PKCι-PAK1 signaling pathways in EGFR and KRAS mutant adenocarcinoma and lung squamous cell carcinoma Ito, Masaoki Codony-Servat, Carles Codony-Servat, Jordi Lligé, David Chaib, Imane Sun, Xiaoyan Miao, Jing Sun, Rongwei Cai, Xueting Verlicchi, Alberto Okada, Morihito Molina-Vila, Miguel Angel Karachaliou, Niki Cao, Peng Rosell, Rafael Cell Commun Signal Research INTRODUCTION: p21-activated kinase 1 (PAK1) stimulates growth and metastasis in non-small cell lung cancer (NSCLC). Protein kinase C iota (PKCι) is an enzyme highly expressed in NSCLC, regulating PAK1 signaling. In the present study we explored whether the PKCι-PAK1 signaling pathway approach can be an efficient target in different types of NSCLC cell and mouse models. METHODS: The effect of IPA-3 (PAK1 inhibitor) plus auranofin (PKCι inhibitor) combination was evaluated by cell viability assay, colony formation and western blotting assay, using three types of NSCLC cell lines: EGFR or KRAS mutant adenocarcinoma and squamous cell carcinoma with PAK1 amplification. In addition, for clinical availability, screening for new PAK1 inhibitors was carried out and the compound OTSSP167 was evaluated in combination with auranofin in cell and mice models. RESULTS: The combination of IPA-3 or OTSSP167 plus auranofin showed high synergism for inhibiting cell viability and colony formation in three cell lines. Mechanistic characterization revealed that this drug combination abrogated expression and activation of membrane receptors and downstream signaling proteins crucial in lung cancer: EGFR, MET, PAK1, PKCι, ERK1/2, AKT, YAP1 and mTOR. A nude mouse xenograft assay demonstrated that this drug combination strongly suppressed tumor volume compared with single drug treatment. CONCLUSIONS: Combination of IPA-3 or OTSSP167 and auranofin was highly synergistic in EGFR or KRAS mutant adenocarcinoma and squamous cell carcinoma cell lines and decreased tumor volume in mice models. It is of interest to further test the targeting of PKCι-PAK1 signaling pathways in EGFR mutant, KRAS mutant and squamous NSCLC patients. BioMed Central 2019-10-28 /pmc/articles/PMC6819333/ /pubmed/31660987 http://dx.doi.org/10.1186/s12964-019-0446-z Text en © The Author(s). 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Ito, Masaoki
Codony-Servat, Carles
Codony-Servat, Jordi
Lligé, David
Chaib, Imane
Sun, Xiaoyan
Miao, Jing
Sun, Rongwei
Cai, Xueting
Verlicchi, Alberto
Okada, Morihito
Molina-Vila, Miguel Angel
Karachaliou, Niki
Cao, Peng
Rosell, Rafael
Targeting PKCι-PAK1 signaling pathways in EGFR and KRAS mutant adenocarcinoma and lung squamous cell carcinoma
title Targeting PKCι-PAK1 signaling pathways in EGFR and KRAS mutant adenocarcinoma and lung squamous cell carcinoma
title_full Targeting PKCι-PAK1 signaling pathways in EGFR and KRAS mutant adenocarcinoma and lung squamous cell carcinoma
title_fullStr Targeting PKCι-PAK1 signaling pathways in EGFR and KRAS mutant adenocarcinoma and lung squamous cell carcinoma
title_full_unstemmed Targeting PKCι-PAK1 signaling pathways in EGFR and KRAS mutant adenocarcinoma and lung squamous cell carcinoma
title_short Targeting PKCι-PAK1 signaling pathways in EGFR and KRAS mutant adenocarcinoma and lung squamous cell carcinoma
title_sort targeting pkcι-pak1 signaling pathways in egfr and kras mutant adenocarcinoma and lung squamous cell carcinoma
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819333/
https://www.ncbi.nlm.nih.gov/pubmed/31660987
http://dx.doi.org/10.1186/s12964-019-0446-z
work_keys_str_mv AT itomasaoki targetingpkcipak1signalingpathwaysinegfrandkrasmutantadenocarcinomaandlungsquamouscellcarcinoma
AT codonyservatcarles targetingpkcipak1signalingpathwaysinegfrandkrasmutantadenocarcinomaandlungsquamouscellcarcinoma
AT codonyservatjordi targetingpkcipak1signalingpathwaysinegfrandkrasmutantadenocarcinomaandlungsquamouscellcarcinoma
AT lligedavid targetingpkcipak1signalingpathwaysinegfrandkrasmutantadenocarcinomaandlungsquamouscellcarcinoma
AT chaibimane targetingpkcipak1signalingpathwaysinegfrandkrasmutantadenocarcinomaandlungsquamouscellcarcinoma
AT sunxiaoyan targetingpkcipak1signalingpathwaysinegfrandkrasmutantadenocarcinomaandlungsquamouscellcarcinoma
AT miaojing targetingpkcipak1signalingpathwaysinegfrandkrasmutantadenocarcinomaandlungsquamouscellcarcinoma
AT sunrongwei targetingpkcipak1signalingpathwaysinegfrandkrasmutantadenocarcinomaandlungsquamouscellcarcinoma
AT caixueting targetingpkcipak1signalingpathwaysinegfrandkrasmutantadenocarcinomaandlungsquamouscellcarcinoma
AT verlicchialberto targetingpkcipak1signalingpathwaysinegfrandkrasmutantadenocarcinomaandlungsquamouscellcarcinoma
AT okadamorihito targetingpkcipak1signalingpathwaysinegfrandkrasmutantadenocarcinomaandlungsquamouscellcarcinoma
AT molinavilamiguelangel targetingpkcipak1signalingpathwaysinegfrandkrasmutantadenocarcinomaandlungsquamouscellcarcinoma
AT karachaliouniki targetingpkcipak1signalingpathwaysinegfrandkrasmutantadenocarcinomaandlungsquamouscellcarcinoma
AT caopeng targetingpkcipak1signalingpathwaysinegfrandkrasmutantadenocarcinomaandlungsquamouscellcarcinoma
AT rosellrafael targetingpkcipak1signalingpathwaysinegfrandkrasmutantadenocarcinomaandlungsquamouscellcarcinoma