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 (2014) Mycobacterium bovis BCG promotes tumor cell survival from tumor necrosis factor-α-induced apoptosis Molecular Cancer, 13 . Article ID 210, 13 pages. ISSN 1476-4598

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Official URL: http://molecular-cancer.biomedcentral.com/articles...

Related URL: http://dx.doi.org/10.1186/1476-4598-13-210

Abstract

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-Guerin (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.

Item Type:Article
Source:Copyright of this article belongs to BioMed Central.
Keywords:p53; TNF-α; Apoptosis; COP1; SHH Signaling; BCG Immunotherapy
ID Code:99592
Deposited On:26 Nov 2016 11:38
Last Modified:26 Nov 2016 11:38

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