title: An Oct-1-based, feed-forward mechanism of apoptosis inhibited by co-culture with Raji B-cells: towards a model of the cancer cell/B-cell microenvironment.
abstract: A continuing conundrum of cancer biology is the dichotomous function of transcription factors that regulate both proliferation and apoptosis, seemingly opposite results. Previous results have indicated that regulated entry into the S-phase of the cell cycle can be anti-apoptotic. Indeed, tumor suppressor genes can be amplified in tumors and certain, slow growing cancers can represent a relatively poor prognosis, both phenomena likely related to reduced cancer cell apoptosis, in turn due to reduced, unproductive entry into S-phase. In this report, we demonstrate that the Oct-1 transcription factor, commonly considered pro-proliferative, indeed facilitates IFN-γ induced apoptosis in 5637 bladder carcinoma cells, consistent with the role of the retinoblastoma protein in down-regulating Oct-1 DNA binding activity and in suppressing IFN-γ induced apoptosis. More importantly, despite the commonly appreciated process of IFN-γ induced apoptosis, IFN-γ at low concentrations stimulated bladder cancer cell proliferation, consistent with apoptosis being dependent on an overstimulation of what is otherwise a pro-proliferative pathway. This observation is in turn consistent with a feed forward mechanism of apoptosis, whereby transcription factors activate proliferation-effector genes at relatively low levels, then apoptosis-effector genes when the transcription factors over-accumulate. Finally, Oct-1 mediated apoptosis is inhibited by co-culture with Raji B-cells, raising the question of whether the normal lymph node environment, or other microenvironments with high concentrations of B-cells, is protective against Oct-1 facilitated apoptosis?
authors.affiliation: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida.
authors.forename: Karoly
authors.initials: K
authors.lastname: Szekeres
authors.affiliation: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida.
authors.forename: Rudra
authors.initials: R
authors.lastname: Koul
authors.affiliation: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida.
authors.forename: James
authors.initials: J
authors.lastname: Mauro
authors.affiliation: Analytic Microscopy Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Lloyd
authors.affiliation: Analytic Microscopy Core, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Johnson
authors.affiliation: Department of Molecular Medicine, Morsani College of Medicine, University of South Florida; Immunology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Electronic address: gblanck@health.usf.edu.
authors.forename: George
authors.initials: G
authors.lastname: Blanck
mesh_terms: D017209:Apoptosis / Q000235:genetics* / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018920:Coculture Techniques; D006801:Humans; D007371:Interferon-gamma; D009369:Neoplasms / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D050811:Octamer Transcription Factor-1 / Q000235:genetics*; D059016:Tumor Microenvironment / Q000235:genetics* / Q000276:immunology
chemical_list: D050811:Octamer Transcription Factor-1; D007371:Interferon-gamma
keywords: B-cell microenvironment; Bladder carcinoma; Feed-forward apoptosis; Interferon-gamma; Oct-1; Transcription factors