Interferon-stimulated gene 15 induces cancer cell death by suppressing the NF-κB signaling pathway

// Hongwu Mao 1, 2, * , Man Wang 1, * , Biyin Cao 1 , Haibin Zhou 2 , Zubin Zhang 1 , Xinliang Mao 1, 3 1 Jiangsu 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 2 Department of Orthopedics, The Second Affiliated Hospital, Soochow University, Suzhou, P.R. China 3 Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, Soochow University, Suzhou, China * These authors contributed equally to this study Correspondence to: Xinliang Mao, email: xinliangmao@suda.edu.cn Zubin Zhang, email: zubinzhang.2008@163.com Keywords: ISG15, NF-κB, apoptosis, cancer Received: April 14, 2016      Accepted: September 14, 2016      Published: September 21, 2016 ABSTRACT 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.