Signaling through IFN regulatory factor-5 sensitizes p53-deficient tumors to DNA damage-induced apoptosis and cell death

Guodong Hu; Margo E Mancl; Betsy J Barnes

doi:10.1158/0008-5472.CAN-05-0583

Signaling through IFN regulatory factor-5 sensitizes p53-deficient tumors to DNA damage-induced apoptosis and cell death

Cancer Res. 2005 Aug 15;65(16):7403-12. doi: 10.1158/0008-5472.CAN-05-0583.

Authors

Guodong Hu¹, Margo E Mancl, Betsy J Barnes

Affiliation

¹ Division of Viral Oncology, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.

PMID: 16103093
DOI: 10.1158/0008-5472.CAN-05-0583

Abstract

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-beta 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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenocarcinoma / drug therapy
Adenocarcinoma / genetics
Adenocarcinoma / metabolism
Adenocarcinoma / pathology*
Antineoplastic Combined Chemotherapy Protocols / pharmacology
Apoptosis / drug effects
Apoptosis / genetics*
Camptothecin / administration & dosage
Camptothecin / analogs & derivatives
Camptothecin / pharmacology
Colonic Neoplasms / drug therapy
Colonic Neoplasms / genetics
Colonic Neoplasms / metabolism
Colonic Neoplasms / pathology*
DNA Damage*
DNA-Binding Proteins / biosynthesis
DNA-Binding Proteins / genetics
DNA-Binding Proteins / physiology*
Drug Synergism
HCT116 Cells
Humans
Interferon Regulatory Factors
Interferon-beta / administration & dosage
Interferon-beta / pharmacology
Irinotecan
Phosphorylation
Signal Transduction
Transcription Factors / biosynthesis
Transcription Factors / genetics
Transcription Factors / physiology*
Transfection
Tumor Suppressor Protein p53 / deficiency*

Substances

DNA-Binding Proteins
IRF5 protein, human
Interferon Regulatory Factors
Transcription Factors
Tumor Suppressor Protein p53
Irinotecan
Interferon-beta
Camptothecin