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Mycobacterium bovis BCG promotes tumor cell survival from tumor necrosis factor-α-induced apoptosis

BACKGROUND: Increased incidence of lung cancer among pulmonary tuberculosis patients suggests mycobacteria-induced tumorigenic response in the host. The alveolar epithelial cells, candidate cells that form lung adenocarcinoma, constitute a niche for mycobacterial replication and infection. We thus e...

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Autores principales: Holla, Sahana, Ghorpade, Devram Sampat, Singh, Vikas, Bansal, Kushagra, Balaji, Kithiganahalli Narayanaswamy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174669/
https://www.ncbi.nlm.nih.gov/pubmed/25208737
http://dx.doi.org/10.1186/1476-4598-13-210
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author Holla, Sahana
Ghorpade, Devram Sampat
Singh, Vikas
Bansal, Kushagra
Balaji, Kithiganahalli Narayanaswamy
author_facet Holla, Sahana
Ghorpade, Devram Sampat
Singh, Vikas
Bansal, Kushagra
Balaji, Kithiganahalli Narayanaswamy
author_sort Holla, Sahana
collection PubMed
description BACKGROUND: Increased incidence of lung cancer among pulmonary tuberculosis patients suggests mycobacteria-induced tumorigenic response in the host. The alveolar epithelial cells, candidate cells that form lung adenocarcinoma, constitute a niche for mycobacterial replication and infection. We thus explored the possible mechanism of M. bovis Bacillus Calmette-Guérin (BCG)-assisted tumorigenicity in type II epithelial cells, human lung adenocarcinoma A549 and other cancer cells. METHODS: Cancer cell lines originating from lung, colon, bladder, liver, breast, skin and cervix were treated with tumor necrosis factor (TNF)-α in presence or absence of BCG infection. p53, COP1 and sonic hedgehog (SHH) signaling markers were determined by immunoblotting and luciferase assays, and quantitative real time PCR was done for p53-responsive pro-apoptotic genes and SHH signaling markers. MTT assays and Annexin V staining were utilized to study apoptosis. Gain- and loss-of-function approaches were used to investigate the role for SHH and COP1 signaling during apoptosis. A549 xenografted mice were used to validate the contribution of BCG during TNF-α treatment. RESULTS: Here, we show that BCG inhibits TNF-α-mediated apoptosis in A549 cells via downregulation of p53 expression. Substantiating this observation, BCG rescued A549 xenografts from TNF-α-mediated tumor clearance in nude mice. Furthermore, activation of SHH signaling by BCG induced the expression of an E3 ubiquitin ligase, COP1. SHH-driven COP1 targeted p53, thereby facilitating downregulation of p53-responsive pro-apoptotic genes and inhibition of apoptosis. Similar effects of BCG could be shown for HCT116, T24, MNT-1, HepG2 and HELA cells but not for HCT116 p53(-/-) and MDA-MB-231 cells. CONCLUSION: Our results not only highlight possible explanations for the coexistence of pulmonary tuberculosis and lung cancer but also address probable reasons for failure of BCG immunotherapy of cancers. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1476-4598-13-210) contains supplementary material, which is available to authorized users.
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spelling pubmed-41746692014-09-26 Mycobacterium bovis BCG promotes tumor cell survival from tumor necrosis factor-α-induced apoptosis Holla, Sahana Ghorpade, Devram Sampat Singh, Vikas Bansal, Kushagra Balaji, Kithiganahalli Narayanaswamy Mol Cancer Research BACKGROUND: Increased incidence of lung cancer among pulmonary tuberculosis patients suggests mycobacteria-induced tumorigenic response in the host. The alveolar epithelial cells, candidate cells that form lung adenocarcinoma, constitute a niche for mycobacterial replication and infection. We thus explored the possible mechanism of M. bovis Bacillus Calmette-Guérin (BCG)-assisted tumorigenicity in type II epithelial cells, human lung adenocarcinoma A549 and other cancer cells. METHODS: Cancer cell lines originating from lung, colon, bladder, liver, breast, skin and cervix were treated with tumor necrosis factor (TNF)-α in presence or absence of BCG infection. p53, COP1 and sonic hedgehog (SHH) signaling markers were determined by immunoblotting and luciferase assays, and quantitative real time PCR was done for p53-responsive pro-apoptotic genes and SHH signaling markers. MTT assays and Annexin V staining were utilized to study apoptosis. Gain- and loss-of-function approaches were used to investigate the role for SHH and COP1 signaling during apoptosis. A549 xenografted mice were used to validate the contribution of BCG during TNF-α treatment. RESULTS: Here, we show that BCG inhibits TNF-α-mediated apoptosis in A549 cells via downregulation of p53 expression. Substantiating this observation, BCG rescued A549 xenografts from TNF-α-mediated tumor clearance in nude mice. Furthermore, activation of SHH signaling by BCG induced the expression of an E3 ubiquitin ligase, COP1. SHH-driven COP1 targeted p53, thereby facilitating downregulation of p53-responsive pro-apoptotic genes and inhibition of apoptosis. Similar effects of BCG could be shown for HCT116, T24, MNT-1, HepG2 and HELA cells but not for HCT116 p53(-/-) and MDA-MB-231 cells. CONCLUSION: Our results not only highlight possible explanations for the coexistence of pulmonary tuberculosis and lung cancer but also address probable reasons for failure of BCG immunotherapy of cancers. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/1476-4598-13-210) contains supplementary material, which is available to authorized users. BioMed Central 2014-09-11 /pmc/articles/PMC4174669/ /pubmed/25208737 http://dx.doi.org/10.1186/1476-4598-13-210 Text en © Holla et al.; licensee BioMed Central Ltd. 2014 This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. 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
Holla, Sahana
Ghorpade, Devram Sampat
Singh, Vikas
Bansal, Kushagra
Balaji, Kithiganahalli Narayanaswamy
Mycobacterium bovis BCG promotes tumor cell survival from tumor necrosis factor-α-induced apoptosis
title Mycobacterium bovis BCG promotes tumor cell survival from tumor necrosis factor-α-induced apoptosis
title_full Mycobacterium bovis BCG promotes tumor cell survival from tumor necrosis factor-α-induced apoptosis
title_fullStr Mycobacterium bovis BCG promotes tumor cell survival from tumor necrosis factor-α-induced apoptosis
title_full_unstemmed Mycobacterium bovis BCG promotes tumor cell survival from tumor necrosis factor-α-induced apoptosis
title_short Mycobacterium bovis BCG promotes tumor cell survival from tumor necrosis factor-α-induced apoptosis
title_sort mycobacterium bovis bcg promotes tumor cell survival from tumor necrosis factor-α-induced apoptosis
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4174669/
https://www.ncbi.nlm.nih.gov/pubmed/25208737
http://dx.doi.org/10.1186/1476-4598-13-210
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