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Alpha1-antitrypsin protects lung cancer cells from staurosporine-induced apoptosis: the role of bacterial lipopolysaccharide

Elevated levels of plasma alpha1-antitrypsin (AAT) correlate with a poor prognosis of various cancers. Herein, we investigated effects of exogenous AAT on non-small lung cancer cell lines with high (H1975) and very low (H661) baseline expression of SERPINA1 gene encoding AAT protein. Comparison of c...

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Autores principales: Schwarz, Natalie, Tumpara, Srinu, Wrenger, Sabine, Ercetin, Evrim, Hamacher, Jürg, Welte, Tobias, Janciauskiene, Sabina
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293251/
https://www.ncbi.nlm.nih.gov/pubmed/32533048
http://dx.doi.org/10.1038/s41598-020-66825-w
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author Schwarz, Natalie
Tumpara, Srinu
Wrenger, Sabine
Ercetin, Evrim
Hamacher, Jürg
Welte, Tobias
Janciauskiene, Sabina
author_facet Schwarz, Natalie
Tumpara, Srinu
Wrenger, Sabine
Ercetin, Evrim
Hamacher, Jürg
Welte, Tobias
Janciauskiene, Sabina
author_sort Schwarz, Natalie
collection PubMed
description Elevated levels of plasma alpha1-antitrypsin (AAT) correlate with a poor prognosis of various cancers. Herein, we investigated effects of exogenous AAT on non-small lung cancer cell lines with high (H1975) and very low (H661) baseline expression of SERPINA1 gene encoding AAT protein. Comparison of cells grown for 3 weeks in a regular medium versus medium supplemented with 2 mg/ml of AAT revealed that in the presence of AAT cells acquire better proliferative properties, resistance to staurosporine (STS)-induced apoptosis, and show higher expression of CLU, a pro-tumorigenic gene coding clusterin protein. Similarly, the co-administration of STS with AAT or addition of AAT to the cells pre-treated with STS abrogated effects of STS in both cell lines. Following experiments with H1975 cells have shown that AAT blocks critical steps in STS-induced cell death: inhibition of AKT/MAPK pathways, and activation of caspase 3 and autophagy. AAT does not inhibit apoptosis-triggered by chloroquine (inhibitor of autophagy) or streptonigrin (inducer of p53 pathway). The anti-apoptotic effects of AAT were unaffected by lipopolysaccharide (LPS). However, AAT induced TLR4 levels and enhanced LPS effects on the production of IL-6, a tumor-promoting cytokine. Our data provide further evidence that AAT plays a significant role in the tumorigenesis.
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spelling pubmed-72932512020-06-15 Alpha1-antitrypsin protects lung cancer cells from staurosporine-induced apoptosis: the role of bacterial lipopolysaccharide Schwarz, Natalie Tumpara, Srinu Wrenger, Sabine Ercetin, Evrim Hamacher, Jürg Welte, Tobias Janciauskiene, Sabina Sci Rep Article Elevated levels of plasma alpha1-antitrypsin (AAT) correlate with a poor prognosis of various cancers. Herein, we investigated effects of exogenous AAT on non-small lung cancer cell lines with high (H1975) and very low (H661) baseline expression of SERPINA1 gene encoding AAT protein. Comparison of cells grown for 3 weeks in a regular medium versus medium supplemented with 2 mg/ml of AAT revealed that in the presence of AAT cells acquire better proliferative properties, resistance to staurosporine (STS)-induced apoptosis, and show higher expression of CLU, a pro-tumorigenic gene coding clusterin protein. Similarly, the co-administration of STS with AAT or addition of AAT to the cells pre-treated with STS abrogated effects of STS in both cell lines. Following experiments with H1975 cells have shown that AAT blocks critical steps in STS-induced cell death: inhibition of AKT/MAPK pathways, and activation of caspase 3 and autophagy. AAT does not inhibit apoptosis-triggered by chloroquine (inhibitor of autophagy) or streptonigrin (inducer of p53 pathway). The anti-apoptotic effects of AAT were unaffected by lipopolysaccharide (LPS). However, AAT induced TLR4 levels and enhanced LPS effects on the production of IL-6, a tumor-promoting cytokine. Our data provide further evidence that AAT plays a significant role in the tumorigenesis. Nature Publishing Group UK 2020-06-12 /pmc/articles/PMC7293251/ /pubmed/32533048 http://dx.doi.org/10.1038/s41598-020-66825-w Text en © The Author(s) 2020 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
Schwarz, Natalie
Tumpara, Srinu
Wrenger, Sabine
Ercetin, Evrim
Hamacher, Jürg
Welte, Tobias
Janciauskiene, Sabina
Alpha1-antitrypsin protects lung cancer cells from staurosporine-induced apoptosis: the role of bacterial lipopolysaccharide
title Alpha1-antitrypsin protects lung cancer cells from staurosporine-induced apoptosis: the role of bacterial lipopolysaccharide
title_full Alpha1-antitrypsin protects lung cancer cells from staurosporine-induced apoptosis: the role of bacterial lipopolysaccharide
title_fullStr Alpha1-antitrypsin protects lung cancer cells from staurosporine-induced apoptosis: the role of bacterial lipopolysaccharide
title_full_unstemmed Alpha1-antitrypsin protects lung cancer cells from staurosporine-induced apoptosis: the role of bacterial lipopolysaccharide
title_short Alpha1-antitrypsin protects lung cancer cells from staurosporine-induced apoptosis: the role of bacterial lipopolysaccharide
title_sort alpha1-antitrypsin protects lung cancer cells from staurosporine-induced apoptosis: the role of bacterial lipopolysaccharide
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293251/
https://www.ncbi.nlm.nih.gov/pubmed/32533048
http://dx.doi.org/10.1038/s41598-020-66825-w
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