Antiproliferative Effects of Interferons against Human Bladder Carcinoma Cell Lines in vitro

Grups, J. W.; Frohmüller, H.

doi:10.1159/000281351

Cited by 17 publications

(6 citation statements)

References 7 publications

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“…Anti-proliferative effects of type I IFN have been reported for diverse cell types, including bladder cancer; however, some of the earlier reports described assays that do not distinguish between cell proliferation arrest and cell death. 13 , 14 , 17 To clarify the effects of type I IFN on proliferation of bladder cancer cells, we chose an assay (5-ethynyl-2′-deoxyuridine [EdU] incorporation) that measures cell-cycle progression rather than cell number, because cell number can be a compound effect of cell proliferation and/or viability. We assembled a panel of 12 diverse human bladder cancer cell lines ( Table 1 ) and the non-transformed immortalized cell line SV-HUC-1, and measured cell-cycle progression from G1 to S phase in response to stimuli.…”

Section: Resultsmentioning

confidence: 99%

Molecular characterization of type I IFN-induced cytotoxicity in bladder cancer cells reveals biomarkers of resistance

Green¹,

Osterhout²,

Klova³

et al. 2021

Molecular Therapy - Oncolytics

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Although anti-tumor activities of type I interferons (IFNs) have been recognized for decades, the molecular mechanisms contributing to clinical response remain poorly understood. The complex functions of these pleiotropic cytokines include stimulation of innate and adaptive immune responses against tumors as well as direct inhibition of tumor cells. In high-grade, Bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer, nadofaragene firadenovec, a non-replicating adenovirus administered locally to express the IFNα2b transgene, embodies a novel approach to deploy the therapeutic activity of type I IFNs while minimizing systemic toxicities. Deciphering which functions of type I IFN are required for clinical activity will bolster efforts to maximize the efficacy of nadofaragene firadenovec and other type I IFN-based therapies, and inform strategies to address resistance. As such, we characterized the phenotypic and molecular response of human bladder cancer cell lines to IFNα delivered in multiple contexts, including adenoviral delivery. We found that constitutive activation of the type I IFN signaling pathway is a biomarker for resistance to both transcriptional response and direct cytotoxic effects of IFNα. We present several genes that discriminate between sensitive and resistant tumor cells, suggesting they should be explored for utility as biomarkers in future clinical trials of type I IFN-based anti-tumor therapies.

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Section: Resultsmentioning

confidence: 99%

Molecular characterization of type I IFN-induced cytotoxicity in bladder cancer cells reveals biomarkers of resistance

Green¹,

Osterhout²,

Klova³

et al. 2021

Molecular Therapy - Oncolytics

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“…Thus, both CD40L and IFN-b confer negative effects on carcinoma growth by improving tumor cell immunogenicity (4,14,15) and triggering direct antiproliferative and proapoptotic properties (37)(38)(39)(40)(41). Both CD40L and type I IFNs also act on immune cells to augment Th1 cell responses, enhance expression of MHC class I molecules, and generate NK and T cellmediated cytotoxicity (reviewed in Refs.…”

Section: Discussionmentioning

confidence: 99%

CD40 Stimulates a “Feed-Forward” NF-κB–Driven Molecular Pathway That Regulates IFN-β Expression in Carcinoma Cells

Moschonas

Ioannou

Eliopoulos

2012

The Journal of Immunology

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IFN-β and the CD40L (CD154) share important roles in the antiviral and antitumor immune responses. In this study, we show that CD40 receptor occupancy results in IFN-β upregulation through an unconventional “feed-forward” mechanism, which is orchestrated by canonical NF-κB and involves the sequential de novo synthesis of IFN regulatory factor (IRF)1 and Viperin (RSAD2), an IRF1 target. RelA (p65) NF-κB, IRF1, and Viperin-dependent IRF7 binding to the IFN-β promoter largely controls its activity. However, full activation of IFN-β also requires the parallel engagement of noncanonical NF-κB2 signaling leading to p52 recruitment to the IFN-β promoter. These data define a novel link between CD40 signaling and IFN-β expression and provide a telling example of how signal propagation can be exploited to ensure efficient regulation of gene expression.

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“…The bladder carcinoma cell lines EJ and VM-CUB-1 (26) were maintained in RPMI medium supplemented with 10% fetal calf serum (FCS). The cervical cancer line HeLa and the human embryonic kidney (HEK) line 293 were cultured in Dulbecco's modified Eagle medium supplemented with 10% FCS (GIBCO).…”

Section: Methodsmentioning

confidence: 99%

CD40 Induces Antigen Transporter and Immunoproteasome Gene Expression in Carcinomas via the Coordinated Action of NF-κB and of NF-κB-Mediated De Novo Synthesis of IRF-1

Moschonas¹,

Kouraki²,

Knox³

et al. 2008

Molecular and Cellular Biology

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Cancer cells may evade immune surveillance as a result of defective antigen processing and presentation. In this study, we demonstrate that CD40 ligation overcomes this defect through the coordinated action of the transcription factors NF-B and interferon regulatory factor 1 (IRF-1). We show that unlike interferon signaling, which triggers the STAT1-mediated transcriptional activation of IRF-1, the ligation of CD40 in carcinomas induces the rapid upregulation of IRF-1 in a STAT1-independent but NF-B-dependent manner. The transcriptional activation of IRF-1 is controlled largely by the recruitment of p65 (RelA) NF-B to the IRF-1 promoter following the engagement of a TAK1/IB kinase ␤/IB␣ signaling pathway downstream of CD40. NF-B and de novo-synthesized IRF-1 converge to regulate the expression of genes involved in antigen processing and transport, as evident from the sequential recruitment of NF-B and IRF-1 to the promoters of the genes encoding transporter for antigen processing 1 (TAP1), TAP2, tapasin, and low-molecular-mass polypeptides LMP2 and LMP10. Moreover, the RNA interference-mediated knockdown of IRF-1 reduced, whereas the inhibition of NF-B abolished, the effects of CD40 on TAP1 and LMP2 upregulation in carcinoma cells. Collectively, these data reveal a novel "feed-forward" mechanism induced by NF-B which ensures that acutely synthesized IRF-1 operates in concert with NF-B to amplify the immunoproteasome and antigenprocessing functions of CD40.Among the nine known members of the interferon regulatory factor (IRF) family of transcription factors, IRF-1 has attracted significant attention as a master regulator of genes involved in the development of innate and adaptive immunity (reviewed in reference 59). Indeed, studies of mice with a null mutation in the irf-1 alleles (irf-1 Ϫ/Ϫ ) have revealed that IRF-1 plays a crucial role in interferon (IFN)-induced antiviral and antibacterial responses. When challenged with pathogens, irf-1 Ϫ/Ϫ mice display compromised Th1 cell differentiation associated with defects in interleukin-12 p35 subunit (IL-12p35) and inducible nitric oxide synthase (iNOS) gene expression in macrophages and concomitant hyporesponsiveness of CD4 ϩ T lymphocytes and natural killer cells to 37). In line with this observation, the promoters of the IL-12p35 and iNOS genes possess functional IRF-1 binding motifs (42). IRF-1 also plays an important role in the transcriptional control of the transporter for antigen processing TAP1 and the immunoproteasome component LMP2 in response to IFN-␥ (41, 68), thereby influencing the presentation of viral and tumor antigens to CD8 ϩ T cells. Moreover, IRF-1 participates in an autoregulatory loop in the context of type I IFN signaling in which IRF-1 is both a target and a transcriptional activator of 20,72).In addition to its role in regulating the immune response to pathogens, IRF-1 has been proposed to function as a tumor suppressor (reviewed in reference 59) and to influence p53 activity (10). Thus, the loss of IRF-1 dramatically exacerbates susceptib...

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Antiproliferative Effects of Interferons against Human Bladder Carcinoma Cell Lines in vitro

Cited by 17 publications

References 7 publications

Molecular characterization of type I IFN-induced cytotoxicity in bladder cancer cells reveals biomarkers of resistance

Molecular characterization of type I IFN-induced cytotoxicity in bladder cancer cells reveals biomarkers of resistance

CD40 Stimulates a “Feed-Forward” NF-κB–Driven Molecular Pathway That Regulates IFN-β Expression in Carcinoma Cells

CD40 Induces Antigen Transporter and Immunoproteasome Gene Expression in Carcinomas via the Coordinated Action of NF-κB and of NF-κB-Mediated De Novo Synthesis of IRF-1

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