Interferon-gamma enhances radiation-induced cell death via downregulation of Chk1.

Abstract

Interferon-gamma (IFNγ) is a cytokine with roles in immune responses as well as in tumor control. Interferon is often used in cancer treatment together with other therapies. Here we report a novel approach to enhancement of cancer cell killing by combined treatment of IFNγ with ionizing radiation. We found that IFNγ treatment alone in HeLa cells induced phosphorylation of Chk1 in a time- and dose-dependent manner, and resulted in cell arrest. Moreover IFNγ treatment was correlated with attenuation of Chk1 as the treatment shortened protein half-life of Chk1. As Chk1 is an essential cell cycle regulator for viability after DNA damage, attenuation of Chk1 by IFNγ pre-treatment in HeLa cells resulted in increased cell death following ionizing radiation about 2-folds than ionizing radiation treatment alone whereas IFNγ treatment alone had little effect on cell death. X-linked inhibitor of apoptosis-associated factor 1 (XAF1), an IFN-induced gene, seems to partly regulate IFNγ-induced Chk1 destabilization and radiation sensitivity because transient depletion of XAF1 by siRNA prevented IFNγ-induced Chk1 attenuation and partly protected cells from IFNγ-enhanced radiation cell killing. Therefore the results provide a novel rationale to combine IFNγ pretreatment and DNA-damaging anti-cancer drugs such as ionizing radiation to enhance cancer cell killing.

• Authors: Kwang Seok Kim, Kyu Jin Choi, Sangwoo Bae
• Journal: Cancer biology & therapy (Cancer Biol Ther) Vol. 13 Issue 11 Pg. 1018-25 (Sep 2012) ISSN: 1555-8576 [Electronic] United States
• PMID: 22825336 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Apoptosis Regulatory Proteins
• Intracellular Signaling Peptides and Proteins
• Neoplasm Proteins
• RNA, Small Interfering
• XAF1 protein, human
• Interferon-gamma
• Protein Kinases
• CHEK1 protein, human
• Checkpoint Kinase 1

Topics

• Adaptor Proteins, Signal Transducing
• Apoptosis Regulatory Proteins
• Cell Cycle (drug effects, radiation effects)
• Cell Death (drug effects, radiation effects)
• Cell Line, Tumor
• Cell Survival
• Checkpoint Kinase 1
• Combined Modality Therapy
• Down-Regulation (drug effects)
• HeLa Cells
• Humans
• Interferon-gamma (pharmacology)
• Intracellular Signaling Peptides and Proteins (deficiency, genetics, metabolism)
• Lung Neoplasms (drug therapy, enzymology, genetics, radiotherapy)
• Neoplasm Proteins (deficiency, genetics, metabolism)
• Phosphorylation (drug effects)
• Protein Kinases (genetics, metabolism)
• RNA, Small Interfering (administration & dosage, genetics)
• Transfection