Disturbance of Tumor Necrosis Factor Alpha-Mediated Beta Interferon Signaling in Cervical Carcinoma Cells

Bachmann, Anastasia; Hanke, Brigitte; Zawatzky, Rainer; Soto, Ubaldo; Riggelen, Jan van; Hausen, Harald zur; Rösl, Frank

doi:10.1128/jvi.76.1.280-291.2002

Cited by 28 publications

(46 citation statements)

References 69 publications

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“…6 EMCV was originally obtained from the American Type Culture Collection (ATTC) and propagated in L-929 cells using a multiplicity of infection (m.o.i.) of 0.1.…”

Section: Cells Culture Viral Infection and Reagentsmentioning

confidence: 99%

“…To quantify the cytolytic effects, the plates were processed as described. 6 Neutralization assay Cells (1 3 10 4 ) were seeded in 96-well plates. Prior the addition of TNF-a, as indicated in the figure legend, the cells were incubated for 1 hr at 37°C with antibodies neutralizing 100 units IFNb (clone 39C, Biotrend, K€ oln, Germany).…”

Section: Antiviral Titration Assaysmentioning

confidence: 99%

“…Proteins were electrotransferred to Immobilon-P membranes (PVDF, Millipore Corporation, Bedford, MA) and probed with the following antibodies: IRF-1 (Santa Cruz, sc-497x), PKR (Santa Cruz, sc-707) or p48 (IRF-9) (Transduction Laboratories, I-29320-050) as described. 6 For reincubation with additional antibodies, the filters were stripped with 200 mM NaOH for 5 min at room temperature. Native 8% polyacrylamide gels were pre-run in 25 mM Tris and 192 mM glycine, pH 8.4 with 1% deoxycholate in the cathode chamber for 40 min at 10 mA.…”

Section: Western Blotting and Native Gel Electrophoresismentioning

confidence: 99%

“…6 For detection of IFN-b, the following primers were used: sense 5 0 -ACTGCCTCAAGGACAG-GATG-3 0 and reverse 5 0 -AAGCAATTGTCCAGTCCCAG-3 0 . The PCR was performed for 40 cycles consisting of: 94°C for 30 sec, 58°C for 45 sec and 72°C for 30 sec.…”

Section: Reverse Transcriptionmentioning

confidence: 99%

“…4 In a previous investigation, we demonstrated that the antiviral effect of TNF-a, which is mediated by IFN-b gene activation, 5 is disturbed in HPV positive cervical carcinoma cells. 6 The reason for this failure is the lack of interferon-regulatory factor (IRF)-1 and p48 (IRF-9) expression, two key regulators, tightly involved in the transcriptional control of the intermediate and the delayed interferon response. 7 IFN-b expression, however, can be re-established in nontumorigenic somatic cell hybrids, suggesting that the antiviral effect of TNF-a is a recessive trait, which can be complemented only by genetic means.…”

mentioning

confidence: 99%

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Genetic redundancy in human cervical carcinoma cells: Identification of cells with “normal” properties

Bachmann

Zawatzky

Rösl

2007

Intl Journal of Cancer

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Although it is generally assumed that cancer arises from a singular cell, a tumor must be considered as a dynamic and emergent biological structure, whose organizing principle is determined by genetic and epigenetic modifications, occurring variably in response to microenvironmental selection conditions. As previously shown, HPV-positive cervical carcinoma cells have lost their ability to induce IFN-b upon TNF-a treatment. However, regarding cancer as a non-linear system, which may, even in the absence of an apparent selection pressure, fluctuate between different ''metastable'' phenotypes, we demonstrate that TNF-a mediated IFN-b induction is not irreversibly disturbed in all cells. Using the IFN-b sensitive Encephalomyocarditis virus (EMCV) as a tool to monitor antiviral activity in long-term established malignant HeLa cells, rare IFN-b expressing clones were rescued from a population of non-responsive and EMCV-sensitive cells. Antiviral activity was mediated by the re-expression of IRF-1 and p48 (IRF-9), both key regulatory molecules normally found to be suppressed in cervical carcinoma cells. Upon inoculating of selected clones into immunocompromised animals, a reduced or even an absence of tumorigenicity of initially highly malignant cells could be discerned. These data indicate that both the absence of interferon signaling and the ability to form tumors were reversed in a minority of cells. We provide a paradigm for the existence of innate genetic redundancy mechanisms, where a particular phenotype persists and can be isolated without application of drugs generally changing the epigenetic context. ' 2007 Wiley-Liss, Inc.Key words: human papillomaviruses; interferon-b regulation; EMCVcytolysis; tumor necrosis factor alpha; redundancy mechanisms; oscillation; chaotic cell systems; tumorigenicity Infections with certain types of human papillomaviruses (HPV) are the major cause for the development of cervical cancer. 1 Epidemiological studies show that immunodeficient women have a significantly higher risk of developing a tumor than age-matched controls. Hence, cancer of the cervix uteri is the final outcome of a long term selection and escape process, where HPV positive cells are no longer controlled by immunological surveillance. 2 Consequently, a physiological intact communication route between inflammatory and HPV-containing cells is an indispensable prerequisite for a proper antiviral response. 3 Targeting IFN-signaling actually provides a general selective advantage for tumor formation, because it favors the disruption of the intercellular cross-talk between HPV positive and immunological effector cells. 4 In a previous investigation, we demonstrated that the antiviral effect of TNF-a, which is mediated by IFN-b gene activation, 5 is disturbed in HPV positive cervical carcinoma cells. 6 The reason for this failure is the lack of interferon-regulatory factor (IRF)-1 and p48 (IRF-9) expression, two key regulators, tightly involved in the transcriptional control of the intermediate and the delayed interfero...

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“…6 EMCV was originally obtained from the American Type Culture Collection (ATTC) and propagated in L-929 cells using a multiplicity of infection (m.o.i.) of 0.1.…”

Section: Cells Culture Viral Infection and Reagentsmentioning

confidence: 99%

Section: Antiviral Titration Assaysmentioning

confidence: 99%

Section: Western Blotting and Native Gel Electrophoresismentioning

confidence: 99%

Section: Reverse Transcriptionmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Genetic redundancy in human cervical carcinoma cells: Identification of cells with “normal” properties

Bachmann

Zawatzky

Rösl

2007

Intl Journal of Cancer

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Interferon receptor expression regulates the antiproliferative effects of interferons on cancer cells and solid tumors

Wagner¹,

Velichko²,

Chesney³

et al. 2004

Intl Journal of Cancer

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In addition to antiviral effects, Type I interferons (IFN) have potent antiproliferative and immunomodulatory activities. Because of these properties IFNs have been evaluated as therapeutics for the treatment of a number of human diseases, including cancer. Currently, IFNs have been shown to be efficacious for the treatment of only a select number of cancers. The reason for this is unclear. Recent evidence has demonstrated that some cancer cell types seem to be defective in their ability to respond to IFN. It has been suggested that defects in IFN signaling is one mechanism by which cancer cells escape responsiveness to Type I IFNs and growth control in general. We report that transfection and enhanced expression of the Type I IFN receptor chain (IFNAR2c) in 3 different human cancer cell lines markedly increases the sensitivity of these cells to the antiproliferative effects of IFNs. In cancer cells transfected with IFNAR2c, dose response curves demonstrate a significant decrease in the concentrations of IFN required to achieve maximum cell death. Furthermore, in these transfected cells, we observe a significant increase in the number of cells undergoing apoptosis, as measured by DNA fragmentation and Caspase 3 activation. In addition, using an in vivo xenograft tumor model we show an increase in the effectiveness of systemically delivered Betaseron™ in decreasing tumor burden in animals in which solid tumors were generated from IFNAR2c transfected cells. These data show that specific regulation of IFN receptor expression can play a major role in determining the clinical outcome of IFN-based cancer therapeutics by regulating the relative sensitivity of cancer cells to IFN-dependent growth control.

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Cervical cancer and CYP2E1 polymorphisms: implications for molecular epidemiology

Ferreira

Catarino

Pereira

et al. 2005

Eur J Clin Pharmacol

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Disturbance of Tumor Necrosis Factor Alpha-Mediated Beta Interferon Signaling in Cervical Carcinoma Cells

Abstract: In the present study we show that malignant human papillomavirus (

Cited by 28 publications

References 69 publications

Genetic redundancy in human cervical carcinoma cells: Identification of cells with “normal” properties

Genetic redundancy in human cervical carcinoma cells: Identification of cells with “normal” properties

Interferon receptor expression regulates the antiproliferative effects of interferons on cancer cells and solid tumors

Cervical cancer and CYP2E1 polymorphisms: implications for molecular epidemiology

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