title: 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: Divisions of Radiation Effects, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea.
authors: Kwang Seok
authors: KS
authors: Kim
authors: Kyu Jin
authors: KJ
authors: Choi
authors: Sangwoo
authors: S
authors: Bae
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D016923:Cell Death / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D002470:Cell Survival; D000071877:Checkpoint Kinase 1; D003131:Combined Modality Therapy; D015536:Down-Regulation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology*; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics / Q000532:radiotherapy*; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D014162:Transfection
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; C417551:XAF1 protein, human; D007371:Interferon-gamma; D011494:Protein Kinases; C000605867:CHEK1 protein, human; D000071877:Checkpoint Kinase 1