Suppression of Type I Interferon Signaling Overcomes Oncogene-Induced Senescence and Mediates Melanoma Development and Progression
| Autor: | Serge Y. Fuchs, Xiaowei Xu, Angela K Brice, John M. Kirkwood, Qiujing Yu, J. Alan Diehl, Yuliya V. Katlinskaya, Daniel P. Beiting, Hallgeir Rui, Diwakar Davar, Kanstantsin V. Katlinski, Constantinos Koumenis, Cindy Sanders, Angelica Ortiz |
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| Jazyk: | angličtina |
| Předmět: |
Male
0301 basic medicine senescence Cell Receptor Interferon alpha-beta Metastasis Mice 0302 clinical medicine Interferon lcsh:QH301-705.5 Cellular Senescence Aged 80 and over Melanoma Middle Aged interferon receptor medicine.anatomical_structure 030220 oncology & carcinogenesis Interferon Type I Melanocytes type I interferon Female Signal transduction Signal Transduction medicine.drug Adult Proto-Oncogene Proteins B-raf Senescence Down-Regulation Biology Article General Biochemistry Genetics and Molecular Biology BRAF 03 medical and health sciences Downregulation and upregulation Cell Line Tumor medicine melanoma Animals Humans metastasis neoplasms Aged medicine.disease Mice Inbred C57BL HEK293 Cells 030104 developmental biology lcsh:Biology (General) Mutation Cancer research Interferon type I |
| Zdroj: | Cell Reports, Vol 15, Iss 1, Pp 171-180 (2016) |
| ISSN: | 2211-1247 |
| DOI: | 10.1016/j.celrep.2016.03.006 |
| Popis: | SummaryOncogene activation induces DNA damage responses and cell senescence. We report a key role of type I interferons (IFNs) in oncogene-induced senescence. IFN signaling-deficient melanocytes expressing activated Braf do not exhibit senescence and develop aggressive melanomas. Restoration of IFN signaling in IFN-deficient melanoma cells induces senescence and suppresses melanoma progression. Additional data from human melanoma patients and mouse transplanted tumor models suggest the importance of non-cell-autonomous IFN signaling. Inactivation of the IFN pathway is mediated by the IFN receptor IFNAR1 downregulation that invariably occurs during melanoma development. Mice harboring an IFNAR1 mutant, which is partially resistant to downregulation, delay melanoma development, suppress metastatic disease, and better respond to BRAF or PD-1 inhibitors. These results suggest that IFN signaling is an important tumor-suppressive pathway that inhibits melanoma development and progression and argue for targeting IFNAR1 downregulation to prevent metastatic disease and improve the efficacy of molecularly target and immune-targeted melanoma therapies. |
| Databáze: | OpenAIRE |
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