Interferon-stimulated gene 15 induces cancer cell death by suppressing the NF-κB signaling pathway
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Hongwu Mao1,2,*, Man Wang1,*, Biyin Cao1, Haibin Zhou2, Zubin Zhang1, Xinliang Mao1,3
1Jiangsu Key Laboratory for Translational Research and Therapeutics of Neuro-Psycho-Diseases, Department of Pharmacology, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, P.R. China
2Department of Orthopedics, The Second Affiliated Hospital, Soochow University, Suzhou, P.R. China
3Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China
*These authors contributed equally to this study
Xinliang Mao, email: email@example.com
Zubin Zhang, email: firstname.lastname@example.org
Keywords: ISG15, NF-κB, apoptosis, cancer
Received: April 14, 2016 Accepted: September 14, 2016 Published: September 21, 2016
Interferon-stimulated gene 15 (ISG15) is an important cytokine that has been reported in carcinogenesis. However, we found that ISG15 and de-ISGylase USP18 were induced by several anti-cancer agents, which was confirmed by both RT-PCR and immunoblotting assays. Further studies demonstrated that ectopic ISG15 and USP18 inhibited proliferation of myeloma, leukemia and cervical cancer cells. More importantly, ISG15 and USP18 induced cancer cell apoptosis. This finding was confirmed in a cervical xenograft model in which cervical cancer growth was suppressed by lentiviral ISG15. In the mechanistic study, ISG15 was found to disrupt the NF-κB signaling pathway by downregulating the expression of IKKβ and p65, phosphorylation of p65 and IκBα. Consistent with this finding, ISG15 suppressed the expression of NF-κB recognition element-driving luciferase and decreased the transcription of XIAP and Mcl-1, two typical genes regulated by NF-κB. Therefore, the present study demonstrated that ISG15 induces cancer cell apoptosis by disrupting the NF-κB signaling pathway. This study highlighted a novel role of ISG15 in tumor suppression.
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