Interferon-stimulated gene 15 induces cancer cell death by suppressing the NF-κB signaling pathway
Hongwu Mao1,2, Man Wang1, Biyin Cao1
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.
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.
Insights
Interferon-stimulated gene 15 (ISG15) and its de-ISGylase USP18 were found to inhibit cancer cell proliferation and induce apoptosis. ISG15 suppresses tumor growth by disrupting the NF-κB signaling pathway, highlighting its novel tumor-suppressive role.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Interferon-stimulated gene 15 (ISG15) has been implicated in carcinogenesis.
- The role of ISG15 and its de-ISGylase USP18 in cancer progression requires further elucidation.
Purpose of the Study:
- To investigate the role of ISG15 and USP18 in cancer.
- To elucidate the underlying molecular mechanisms of ISG15-mediated tumor suppression.
Main Methods:
- Reverse transcription-polymerase chain reaction (RT-PCR) and immunoblotting assays.
- In vitro cell proliferation and apoptosis assays in myeloma, leukemia, and cervical cancer cell lines.
- In vivo cervical cancer xenograft model.
- Analysis of the NF-κB signaling pathway.
Main Results:
- ISG15 and USP18 were induced by anti-cancer agents and inhibited proliferation of various cancer cells.
- Ectopic ISG15 and USP18 induced cancer cell apoptosis, confirmed in a cervical xenograft model.
- ISG15 disrupted the NF-κB signaling pathway by downregulating IKKβ and p65, and suppressing NF-κB-driven transcription.
Conclusions:
- ISG15 induces cancer cell apoptosis through the disruption of the NF-κB signaling pathway.
- ISG15 exhibits a novel tumor-suppressive role, making it a potential therapeutic target.
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