51. Identification of MYC as an antinecroptotic protein that stifles RIPK1-RIPK3 complex formation.
- Author
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Seong D, Jeong M, Seo J, Lee JY, Hwang CH, Shin HC, Shin JY, Nam YW, Jo JY, Lee H, Kim HJ, Kim HR, Oh JH, Ha SJ, Kim SJ, Roe JS, Kim W, Cheong JW, Bae KH, Lee SC, Oberst A, Vandenabeele P, Shin DH, Lee EW, and Song J
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation, Female, Humans, Leukemia genetics, Leukemia physiopathology, Mice, Mice, Inbred BALB C, Necroptosis, Protein Binding, Protein Transport, Proto-Oncogene Proteins c-myc genetics, Receptor-Interacting Protein Serine-Threonine Kinases genetics, Signal Transduction, Leukemia metabolism, Proto-Oncogene Proteins c-myc metabolism, Receptor-Interacting Protein Serine-Threonine Kinases metabolism
- Abstract
The underlying mechanism of necroptosis in relation to cancer is still unclear. Here, MYC, a potent oncogene, is an antinecroptotic factor that directly suppresses the formation of the RIPK1-RIPK3 complex. Gene set enrichment analyses reveal that the MYC pathway is the most prominently down-regulated signaling pathway during necroptosis. Depletion or deletion of MYC promotes the RIPK1-RIPK3 interaction, thereby stabilizing the RIPK1 and RIPK3 proteins and facilitating necroptosis. Interestingly, MYC binds to RIPK3 in the cytoplasm and inhibits the interaction between RIPK1 and RIPK3 in vitro. Furthermore, MYC-nick, a truncated form that is mainly localized in the cytoplasm, prevented TNF-induced necroptosis. Finally, down-regulation of MYC enhances necroptosis in leukemia cells and suppresses tumor growth in a xenograft model upon treatment with birinapant and emricasan. MYC-mediated suppression of necroptosis is a mechanism of necroptosis resistance in cancer, and approaches targeting MYC to induce necroptosis represent an attractive therapeutic strategy for cancer., Competing Interests: The authors declare no competing interest., (Copyright © 2020 the Author(s). Published by PNAS.)
- Published
- 2020
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