Abstract
BackgroundIncreased 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.MethodsCancer 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.ResultsHere, 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.ConclusionOur 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 materialThe online version of this article (doi:10.1186/1476-4598-13-210) contains supplementary material, which is available to authorized users.
Highlights
Increased incidence of lung cancer among pulmonary tuberculosis patients suggests mycobacteria-induced tumorigenic response in the host
Bacillus Calmette-Guérin (BCG) targets p53 to rescue tumor necrosis factor (TNF)-α-mediated cell death To investigate the effect of mycobacterial infection on the tumorigenic properties of alveolar epithelial cells, we performed co-treatment of A549 cells with BCG and TNF-α, a primary cytokine produced during infection [4]
Infection of A549 cells with BCG decreased the expression of TNF-α-stimulated p53 (Figure 1C). p53 promoter reporter analysis confirmed the same (Figure 1D). p53 is a tumor suppressor that has been strongly implicated in the process of cell death, especially apoptosis [12]
Summary
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. Along with the alveolar macrophages, they are reservoirs for the pathogenic mycobacteria in the lungs; a site suitable for mycobacterial replication [1,2]. These epithelial cells secrete several cytokines and chemokines that orchestrate the early host immune responses and establish the intra-alveolar cytokine network [3]. One of the early cytokines that could regulate epithelial responses during mycobacterial infection is tumor necrosis factor (TNF)-α [4]. TNF-α displays potent anti-tumorigenic properties and used in the treatment of metastatic melanomas, primary or metastatic unresectable liver tumors and soft tissue sarcomas [6,7]
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