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Signaling through IFN Regulatory Factor-5 Sensitizes p53-Deficient Tumors to DNA Damage–Induced Apoptosis and Cell Death

Division of Viral Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland

Requests for reprints: Betsy J. Barnes, The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, 1650 Orleans Street, Baltimore, MD 21231. Phone: 443-287-2758; Fax: 410-955-0840; E-mail: barnebe{at}jhmi.edu.

Human IFN regulatory factor-5 (IRF-5) is a candidate tumor suppressor gene that mediates cell arrest, apoptosis, and immune activation. Here we show that ectopic IRF-5 sensitizes p53-proficient and p53-deficient colon cancer cells to DNA damage–induced apoptosis. The combination IFN-ß and irinotecan (CPT-11) cooperatively inhibits cell growth and IRF-5 synergizes with it to further promote apoptosis. The synergism is due to IRF-5 signaling since a striking defect in apoptosis and cell death was observed in IRF-5-deficient cells, which correlated well with a reduction in DNA damage–induced cellular events. Components of this IRF-5 signaling pathway are investigated including a mechanism for DNA damage–induced IRF-5 activation. Thus, IRF-5–regulated pathways may serve as a target for cancer therapeutics.

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