期刊
PIGMENT CELL & MELANOMA RESEARCH
卷 27, 期 6, 页码 1117-1125出版社
WILEY
DOI: 10.1111/pcmr.12295
关键词
bromodomain and extra-terminal; melanoma; NF-kappaB; cytokine; chemokine; cancer
资金
- Victorian Government through the Victorian Cancer Agency Translational Research Program [EOI09_27]
- National Health and Medical Research Council of Australia (NHMRC) [APP1053792, 1002654]
- NHMRC
The transcription factor NF-kappaB (NF-kB) is a key regulator of cytokine and chemokine production in melanoma and is responsible for symptoms such as anorexia, fatigue, and weight loss. In addition, NF-kB is believed to contribute to progression of the disease by upregulation of cell cycle and anti-apoptotic genes and to contribute to resistance against targeted therapies and immunotherapy. In this study, we have examined the ability of the bromodomain and extra-terminal (BET) protein inhibitor I-BET151 to inhibit NF-kB in melanoma cells. We show that I-BET151 is a potent, selective inhibitor of a number of NF-kB target genes involved in induction of inflammation and cell cycle regulation and downregulates production of cytokines such as IL-6 and IL-8. SiRNA studies indicate that BRD2 is the main BET protein involved in regulation of NF-kB and that I-BET151 caused transcriptional downregulation of the NF-kB subunit p105/p50. These results suggest that BET inhibitors may have an important role in treatment of melanoma where activation of NF-kB may have a key pathogenic role.
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