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Chronic p27(Kip1) Induction by Dexamethasone Causes Senescence Phenotype and Permanent Cell Cycle Blockade in Lung Adenocarcinoma Cells Over-expressing Glucocorticoid Receptor

Dexamethasone (Dex), co-administered to lung adenocarcinoma patients with pemetrexed chemotherapy, protects against pemetrexed cytotoxicity by inducing reversible G1 arrest, reflected by the effect of Dex on FLT-PET images of patient tumors. However, perioperative Dex treatment increases survival bu...

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Autores principales: Patki, Mugdha, McFall, Thomas, Rosati, Rayna, Huang, Yanfang, Malysa, Agnes, Polin, Lisa, Fielder, Abigail, Wilson, Mike R., Lonardo, Fulvio, Back, Jessica, Li, Jing, Matherly, Larry H., Bepler, Gerold, Ratnam, Manohar
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207728/
https://www.ncbi.nlm.nih.gov/pubmed/30375484
http://dx.doi.org/10.1038/s41598-018-34475-8
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author Patki, Mugdha
McFall, Thomas
Rosati, Rayna
Huang, Yanfang
Malysa, Agnes
Polin, Lisa
Fielder, Abigail
Wilson, Mike R.
Lonardo, Fulvio
Back, Jessica
Li, Jing
Matherly, Larry H.
Bepler, Gerold
Ratnam, Manohar
author_facet Patki, Mugdha
McFall, Thomas
Rosati, Rayna
Huang, Yanfang
Malysa, Agnes
Polin, Lisa
Fielder, Abigail
Wilson, Mike R.
Lonardo, Fulvio
Back, Jessica
Li, Jing
Matherly, Larry H.
Bepler, Gerold
Ratnam, Manohar
author_sort Patki, Mugdha
collection PubMed
description Dexamethasone (Dex), co-administered to lung adenocarcinoma patients with pemetrexed chemotherapy, protects against pemetrexed cytotoxicity by inducing reversible G1 arrest, reflected by the effect of Dex on FLT-PET images of patient tumors. However, perioperative Dex treatment increases survival but the mechanism is unknown. In cells with glucocorticoid receptor-α (GR) expression corresponding to higher clinical tumor levels, Dex-induced growth arrest was followed by marked cell expansion, beta-galactosidase expression and Ki67 negativity, despite variable p53 and K-RAS status. Dex induced a transient early surge in p21(Cip1). However, a progressive, irreversible loss of clonogenic growth, whose time of onset was dependent on GR level and Dex dose, was independent of p21(Cip1)and caused by gradual accumulation of p27(Kip1) due to transcriptional activation of p27(Kip1) by Dex. This effect was independent of canonical pathways of senescence or p27(Kip1) regulation. The in vitro observations were reflected by growth suppression and P27(Kip1) induction in GR-overexpressing tumor xenografts compared with isogenic low-GR tumors. Extended Dex treatment induces irreversible cell cycle blockade and a senescence phenotype through chronic activation of the p27(Kip1) gene in GR overexpressing lung tumor cell populations and hence could improve outcome of surgery/pemetrexed chemotherapy and sensitize tumors to immunotherapy.
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spelling pubmed-62077282018-11-01 Chronic p27(Kip1) Induction by Dexamethasone Causes Senescence Phenotype and Permanent Cell Cycle Blockade in Lung Adenocarcinoma Cells Over-expressing Glucocorticoid Receptor Patki, Mugdha McFall, Thomas Rosati, Rayna Huang, Yanfang Malysa, Agnes Polin, Lisa Fielder, Abigail Wilson, Mike R. Lonardo, Fulvio Back, Jessica Li, Jing Matherly, Larry H. Bepler, Gerold Ratnam, Manohar Sci Rep Article Dexamethasone (Dex), co-administered to lung adenocarcinoma patients with pemetrexed chemotherapy, protects against pemetrexed cytotoxicity by inducing reversible G1 arrest, reflected by the effect of Dex on FLT-PET images of patient tumors. However, perioperative Dex treatment increases survival but the mechanism is unknown. In cells with glucocorticoid receptor-α (GR) expression corresponding to higher clinical tumor levels, Dex-induced growth arrest was followed by marked cell expansion, beta-galactosidase expression and Ki67 negativity, despite variable p53 and K-RAS status. Dex induced a transient early surge in p21(Cip1). However, a progressive, irreversible loss of clonogenic growth, whose time of onset was dependent on GR level and Dex dose, was independent of p21(Cip1)and caused by gradual accumulation of p27(Kip1) due to transcriptional activation of p27(Kip1) by Dex. This effect was independent of canonical pathways of senescence or p27(Kip1) regulation. The in vitro observations were reflected by growth suppression and P27(Kip1) induction in GR-overexpressing tumor xenografts compared with isogenic low-GR tumors. Extended Dex treatment induces irreversible cell cycle blockade and a senescence phenotype through chronic activation of the p27(Kip1) gene in GR overexpressing lung tumor cell populations and hence could improve outcome of surgery/pemetrexed chemotherapy and sensitize tumors to immunotherapy. Nature Publishing Group UK 2018-10-30 /pmc/articles/PMC6207728/ /pubmed/30375484 http://dx.doi.org/10.1038/s41598-018-34475-8 Text en © The Author(s) 2018 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Patki, Mugdha
McFall, Thomas
Rosati, Rayna
Huang, Yanfang
Malysa, Agnes
Polin, Lisa
Fielder, Abigail
Wilson, Mike R.
Lonardo, Fulvio
Back, Jessica
Li, Jing
Matherly, Larry H.
Bepler, Gerold
Ratnam, Manohar
Chronic p27(Kip1) Induction by Dexamethasone Causes Senescence Phenotype and Permanent Cell Cycle Blockade in Lung Adenocarcinoma Cells Over-expressing Glucocorticoid Receptor
title Chronic p27(Kip1) Induction by Dexamethasone Causes Senescence Phenotype and Permanent Cell Cycle Blockade in Lung Adenocarcinoma Cells Over-expressing Glucocorticoid Receptor
title_full Chronic p27(Kip1) Induction by Dexamethasone Causes Senescence Phenotype and Permanent Cell Cycle Blockade in Lung Adenocarcinoma Cells Over-expressing Glucocorticoid Receptor
title_fullStr Chronic p27(Kip1) Induction by Dexamethasone Causes Senescence Phenotype and Permanent Cell Cycle Blockade in Lung Adenocarcinoma Cells Over-expressing Glucocorticoid Receptor
title_full_unstemmed Chronic p27(Kip1) Induction by Dexamethasone Causes Senescence Phenotype and Permanent Cell Cycle Blockade in Lung Adenocarcinoma Cells Over-expressing Glucocorticoid Receptor
title_short Chronic p27(Kip1) Induction by Dexamethasone Causes Senescence Phenotype and Permanent Cell Cycle Blockade in Lung Adenocarcinoma Cells Over-expressing Glucocorticoid Receptor
title_sort chronic p27(kip1) induction by dexamethasone causes senescence phenotype and permanent cell cycle blockade in lung adenocarcinoma cells over-expressing glucocorticoid receptor
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6207728/
https://www.ncbi.nlm.nih.gov/pubmed/30375484
http://dx.doi.org/10.1038/s41598-018-34475-8
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