Retinoic Acid affects Lung Adenocarcinoma growth by inducing differentiation via GATA6 activation and EGFR and Wnt inhibition

Abstract A fundamental task in cancer research aims at the identification of new pharmacological therapies that can affect tumor growth. Differentiation therapy might exploit this function not only for hematological diseases, such as acute promyelocytic leukemia (APML) but also for epithelial tumors...

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Autores principales:	Giovanni Zito, Flores Naselli, Laura Saieva, Stefania Raimondo, Giovanna Calabrese, Claudio Guzzardo, Stefano Forte, Christian Rolfo, Rosalba Parenti, Riccardo Alessandro
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/697e75a7031f40699836c5ea19d40037
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spelling	oai:doaj.org-article:697e75a7031f40699836c5ea19d400372021-12-02T12:31:58ZRetinoic Acid affects Lung Adenocarcinoma growth by inducing differentiation via GATA6 activation and EGFR and Wnt inhibition10.1038/s41598-017-05047-z2045-2322https://doaj.org/article/697e75a7031f40699836c5ea19d400372017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-05047-zhttps://doaj.org/toc/2045-2322Abstract A fundamental task in cancer research aims at the identification of new pharmacological therapies that can affect tumor growth. Differentiation therapy might exploit this function not only for hematological diseases, such as acute promyelocytic leukemia (APML) but also for epithelial tumors, including lung cancer. Here we show that Retinoic Acid (RA) arrests in vitro and in vivo the growth of Tyrosine Kinase Inhibitors (TKI) resistant Non Small Cell Lung Cancer (NSCLC). In particular, we found that RA induces G0/G1 cell cycle arrest in TKI resistant NSCLC cells and activates terminal differentiation programs by modulating the expression of GATA6, a key transcription factor involved in the physiological differentiation of the distal lung. In addition, our results demonstrate that RA inhibits EGFR and Wnt signaling activation, two pathways involved in NSCLC progression. Furthermore, we uncovered a novel mechanism in NSCLC that shows how RA exerts its function; we found that RA-mediated GATA6 activation is necessary for EGFR and Wnt inhibition, thus leading to 1) increased differentiation and 2) loss of proliferation. All together, these findings prove that differentiation therapy might be feasible in TKI resistant NSCLCs, and shed light on new targets to define new pharmacological therapies.Giovanni ZitoFlores NaselliLaura SaievaStefania RaimondoGiovanna CalabreseClaudio GuzzardoStefano ForteChristian RolfoRosalba ParentiRiccardo AlessandroNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Giovanni Zito Flores Naselli Laura Saieva Stefania Raimondo Giovanna Calabrese Claudio Guzzardo Stefano Forte Christian Rolfo Rosalba Parenti Riccardo Alessandro Retinoic Acid affects Lung Adenocarcinoma growth by inducing differentiation via GATA6 activation and EGFR and Wnt inhibition
description	Abstract A fundamental task in cancer research aims at the identification of new pharmacological therapies that can affect tumor growth. Differentiation therapy might exploit this function not only for hematological diseases, such as acute promyelocytic leukemia (APML) but also for epithelial tumors, including lung cancer. Here we show that Retinoic Acid (RA) arrests in vitro and in vivo the growth of Tyrosine Kinase Inhibitors (TKI) resistant Non Small Cell Lung Cancer (NSCLC). In particular, we found that RA induces G0/G1 cell cycle arrest in TKI resistant NSCLC cells and activates terminal differentiation programs by modulating the expression of GATA6, a key transcription factor involved in the physiological differentiation of the distal lung. In addition, our results demonstrate that RA inhibits EGFR and Wnt signaling activation, two pathways involved in NSCLC progression. Furthermore, we uncovered a novel mechanism in NSCLC that shows how RA exerts its function; we found that RA-mediated GATA6 activation is necessary for EGFR and Wnt inhibition, thus leading to 1) increased differentiation and 2) loss of proliferation. All together, these findings prove that differentiation therapy might be feasible in TKI resistant NSCLCs, and shed light on new targets to define new pharmacological therapies.
format	article
author	Giovanni Zito Flores Naselli Laura Saieva Stefania Raimondo Giovanna Calabrese Claudio Guzzardo Stefano Forte Christian Rolfo Rosalba Parenti Riccardo Alessandro
author_facet	Giovanni Zito Flores Naselli Laura Saieva Stefania Raimondo Giovanna Calabrese Claudio Guzzardo Stefano Forte Christian Rolfo Rosalba Parenti Riccardo Alessandro
author_sort	Giovanni Zito
title	Retinoic Acid affects Lung Adenocarcinoma growth by inducing differentiation via GATA6 activation and EGFR and Wnt inhibition
title_short	Retinoic Acid affects Lung Adenocarcinoma growth by inducing differentiation via GATA6 activation and EGFR and Wnt inhibition
title_full	Retinoic Acid affects Lung Adenocarcinoma growth by inducing differentiation via GATA6 activation and EGFR and Wnt inhibition
title_fullStr	Retinoic Acid affects Lung Adenocarcinoma growth by inducing differentiation via GATA6 activation and EGFR and Wnt inhibition
title_full_unstemmed	Retinoic Acid affects Lung Adenocarcinoma growth by inducing differentiation via GATA6 activation and EGFR and Wnt inhibition
title_sort	retinoic acid affects lung adenocarcinoma growth by inducing differentiation via gata6 activation and egfr and wnt inhibition
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/697e75a7031f40699836c5ea19d40037
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Retinoic Acid affects Lung Adenocarcinoma growth by inducing differentiation via GATA6 activation and EGFR and Wnt inhibition

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