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IRF-1 reverts the transformed phenotype of oncogenically transformed cells in vitro and in vivo

Oncogene volume 22, pages 1045–1056 (2003)Cite this article

Abstract

The expression of the transcriptional activator and tumor suppressor IRF-1 induces multiple effects that counteract the growth of tumor cells in vitro and in vivo. These include the inhibition of cell proliferation, the secretion of interferon-β (IFN-β), the induction of apoptosis specifically in certain cell types and the induction of a strong T-cell response. Here, we show that apart from its immune-activating properties, IRF-1 expression leads to a reversion of the tumorigenic phenotype of NIH3T3 cells transformed by different oncogenes. This was analysed in detail in a cell line in which the expression of c-Ha-ras and c-myc is under the control of a doxycycline-regulated promoter allowing to switch between the normal and oncogenic cell status. In the same cells, a β-estradiol activatable IRF-1 fusion protein is expressed. After IRF-1 activation the oncogene-mediated acceleration of the cell cycle is reverted. Further, a complete IRF-1-mediated reversion of the oncogenic phenotype is observed in soft-agar growth assays. IRF-1 activation induces IFN-β secretion; however, the observed effects are not mediated by IFN-β. Inhibition of tumor growth is observed in nude mice as long as IRF-1 is active, indicating that neither B- nor T-cells must become activated for tumor growth suppression.

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Abbreviations

EGFR:

epidermal growth factor receptor

HER:

hormone-binding domain of the human estrogen receptor

ISRE:

interferon-stimulated recognition element

IFN-β:

interferon beta

IRF-1:

interferon regulatory factor 1

STAT:

signal transducers and activators of transcription

GAS:

gamma-interferon activated sequence

E2:

β-estradiol

Dox:

doxycycline

MAB:

monoclonal antibody

w.t.:

wild type

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Acknowledgements

We thank M Grashoff and M Höxter for excellent technical support. We gratefully acknowledge the gift of anti-interferon β antibodies by R Zawatzky, Heidelberg. This work has been supported by DFG through SFB 566 (project B7).

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Authors and Affiliations

  1. Department of Gene Regulation and Differentiation, GBF – German Research Center for Biotechnology, Mascheroder Weg 1, Braunschweig, D 38124, Germany

    Andrea Kröger, Andreas Dallügge, Sabine Kirchhoff & Hansjörg Hauser

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  1. Andrea Kröger
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  2. Andreas Dallügge
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Correspondence to Hansjörg Hauser.

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Kröger, A., Dallügge, A., Kirchhoff, S. et al. IRF-1 reverts the transformed phenotype of oncogenically transformed cells in vitro and in vivo. Oncogene 22, 1045–1056 (2003). https://doi.org/10.1038/sj.onc.1206260

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