title: Mycobacterium bovis BCG promotes tumor cell survival from tumor necrosis factor-α-induced apoptosis.
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-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.
  
  
  CONCLUSIONS
  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.
authors.forename: Sahana
authors.initials: S
authors.lastname: Holla
authors.forename: Devram Sampat
authors.initials: DS
authors.lastname: Ghorpade
authors.forename: Vikas
authors.initials: V
authors.lastname: Singh
authors.forename: Kushagra
authors.initials: K
authors.lastname: Bansal
authors.affiliation: Department of Microbiology and Cell Biology, Indian Institute of Science, Bangalore 560012, India. balaji@mcbl.iisc.ernet.in.
authors.forename: Kithiganahalli Narayanaswamy
authors.initials: KN
authors.lastname: Balaji
mesh_terms: D000818:Animals; D017209:Apoptosis; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D045325:HCT116 Cells; D006367:HeLa Cells; D056945:Hep G2 Cells; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009163:Mycobacterium bovis / Q000502:physiology*; D009369:Neoplasms / Q000382:microbiology / Q000473:pathology*; D009374:Neoplasms, Experimental; D015398:Signal Transduction / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D014409:Tumor Necrosis Factor-alpha; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases