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Activity and molecular targets of pioglitazone via blockade of proliferation, invasiveness and bioenergetics in human NSCLC

BACKGROUND: Pioglitazone, a synthetic peroxisome proliferator activated receptor (PPAR-γ) ligand, is known as an antidiabetic drug included in the thiazolidinediones (TZDs) class. It regulates the lipid and glucose cell metabolism and recently a role in the inhibition of numerous cancer cell process...

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Autores principales: Ciaramella, Vincenza, Sasso, Ferdinando Carlo, Di Liello, Raimondo, Corte, Carminia Maria Della, Barra, Giusi, Viscardi, Giuseppe, Esposito, Giovanna, Sparano, Francesca, Troiani, Teresa, Martinelli, Erika, Orditura, Michele, De Vita, Ferdinando, Ciardiello, Fortunato, Morgillo, Floriana
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485164/
https://www.ncbi.nlm.nih.gov/pubmed/31027492
http://dx.doi.org/10.1186/s13046-019-1176-1
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author Ciaramella, Vincenza
Sasso, Ferdinando Carlo
Di Liello, Raimondo
Corte, Carminia Maria Della
Barra, Giusi
Viscardi, Giuseppe
Esposito, Giovanna
Sparano, Francesca
Troiani, Teresa
Martinelli, Erika
Orditura, Michele
De Vita, Ferdinando
Ciardiello, Fortunato
Morgillo, Floriana
author_facet Ciaramella, Vincenza
Sasso, Ferdinando Carlo
Di Liello, Raimondo
Corte, Carminia Maria Della
Barra, Giusi
Viscardi, Giuseppe
Esposito, Giovanna
Sparano, Francesca
Troiani, Teresa
Martinelli, Erika
Orditura, Michele
De Vita, Ferdinando
Ciardiello, Fortunato
Morgillo, Floriana
author_sort Ciaramella, Vincenza
collection PubMed
description BACKGROUND: Pioglitazone, a synthetic peroxisome proliferator activated receptor (PPAR-γ) ligand, is known as an antidiabetic drug included in the thiazolidinediones (TZDs) class. It regulates the lipid and glucose cell metabolism and recently a role in the inhibition of numerous cancer cell processes has been described. METHODS: In our work we investigate the anti-tumor effects of pioglitazone in in vitro models of non small cell lung cancer (NSCLC) and also, we generated ex-vivo three-dimensional (3D) cultures from human lung adenocarcinoma (ADK) as a model to test drug efficacy observed in vitro. The inhibitory effect of pioglitazone on cell proliferation, apoptosis and cell invasion in a panel of human NSCLC cell lines was evaluated by multiple assays. RESULTS: Pioglitazone reduced proliferative and invasive abilities with an IC(50) ranging between 5 and 10 μM and induced apoptosis of NSCLC cells. mRNA microarray expression profiling showed a down regulation of MAPK, Myc and Ras genes after treatment with pioglitazone; altered gene expression was confirmed by protein analysis in a dose-related reduction of survivin and phosphorylated proteins levels of MAPK pathway. Interestingly mRNA microarray analysis showed also that pioglitazone affects TGFβ pathway, which is important in the epithelial-to-mesenchimal transition (EMT) process, by down-regulating TGFβR1 and SMAD3 mRNA expression. In addition, extracellular acidification rate (ECAR) and a proportional reduction of markers of altered glucose metabolism in treated cells demonstrated also cell bioenergetics modulation by pioglitazone. CONCLUSIONS: Data indicate that PPAR-γ agonists represent an attractive treatment tool and by suppression of cell growth (in vitro and ex vivo models) and of invasion via blockade of MAPK cascade and TGFβ/SMADs signaling, respectively, and its role in cancer bioenergetics and metabolism indicate that PPAR-γ agonists represent an attractive treatment tool for NSCLC.
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spelling pubmed-64851642019-05-03 Activity and molecular targets of pioglitazone via blockade of proliferation, invasiveness and bioenergetics in human NSCLC Ciaramella, Vincenza Sasso, Ferdinando Carlo Di Liello, Raimondo Corte, Carminia Maria Della Barra, Giusi Viscardi, Giuseppe Esposito, Giovanna Sparano, Francesca Troiani, Teresa Martinelli, Erika Orditura, Michele De Vita, Ferdinando Ciardiello, Fortunato Morgillo, Floriana J Exp Clin Cancer Res Research BACKGROUND: Pioglitazone, a synthetic peroxisome proliferator activated receptor (PPAR-γ) ligand, is known as an antidiabetic drug included in the thiazolidinediones (TZDs) class. It regulates the lipid and glucose cell metabolism and recently a role in the inhibition of numerous cancer cell processes has been described. METHODS: In our work we investigate the anti-tumor effects of pioglitazone in in vitro models of non small cell lung cancer (NSCLC) and also, we generated ex-vivo three-dimensional (3D) cultures from human lung adenocarcinoma (ADK) as a model to test drug efficacy observed in vitro. The inhibitory effect of pioglitazone on cell proliferation, apoptosis and cell invasion in a panel of human NSCLC cell lines was evaluated by multiple assays. RESULTS: Pioglitazone reduced proliferative and invasive abilities with an IC(50) ranging between 5 and 10 μM and induced apoptosis of NSCLC cells. mRNA microarray expression profiling showed a down regulation of MAPK, Myc and Ras genes after treatment with pioglitazone; altered gene expression was confirmed by protein analysis in a dose-related reduction of survivin and phosphorylated proteins levels of MAPK pathway. Interestingly mRNA microarray analysis showed also that pioglitazone affects TGFβ pathway, which is important in the epithelial-to-mesenchimal transition (EMT) process, by down-regulating TGFβR1 and SMAD3 mRNA expression. In addition, extracellular acidification rate (ECAR) and a proportional reduction of markers of altered glucose metabolism in treated cells demonstrated also cell bioenergetics modulation by pioglitazone. CONCLUSIONS: Data indicate that PPAR-γ agonists represent an attractive treatment tool and by suppression of cell growth (in vitro and ex vivo models) and of invasion via blockade of MAPK cascade and TGFβ/SMADs signaling, respectively, and its role in cancer bioenergetics and metabolism indicate that PPAR-γ agonists represent an attractive treatment tool for NSCLC. BioMed Central 2019-04-26 /pmc/articles/PMC6485164/ /pubmed/31027492 http://dx.doi.org/10.1186/s13046-019-1176-1 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
Ciaramella, Vincenza
Sasso, Ferdinando Carlo
Di Liello, Raimondo
Corte, Carminia Maria Della
Barra, Giusi
Viscardi, Giuseppe
Esposito, Giovanna
Sparano, Francesca
Troiani, Teresa
Martinelli, Erika
Orditura, Michele
De Vita, Ferdinando
Ciardiello, Fortunato
Morgillo, Floriana
Activity and molecular targets of pioglitazone via blockade of proliferation, invasiveness and bioenergetics in human NSCLC
title Activity and molecular targets of pioglitazone via blockade of proliferation, invasiveness and bioenergetics in human NSCLC
title_full Activity and molecular targets of pioglitazone via blockade of proliferation, invasiveness and bioenergetics in human NSCLC
title_fullStr Activity and molecular targets of pioglitazone via blockade of proliferation, invasiveness and bioenergetics in human NSCLC
title_full_unstemmed Activity and molecular targets of pioglitazone via blockade of proliferation, invasiveness and bioenergetics in human NSCLC
title_short Activity and molecular targets of pioglitazone via blockade of proliferation, invasiveness and bioenergetics in human NSCLC
title_sort activity and molecular targets of pioglitazone via blockade of proliferation, invasiveness and bioenergetics in human nsclc
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6485164/
https://www.ncbi.nlm.nih.gov/pubmed/31027492
http://dx.doi.org/10.1186/s13046-019-1176-1
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