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    Induction of IRAK-M in melanoma induces caspase-3 dependent apoptosis by reducing TRAF6 and calpastatin levels

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    Author
    Ciavattone, N.
    Younis, R.
    Wang, L.
    Zhang, Y.
    Davila, E.
    Date
    2020
    Journal
    Communications Biology
    Publisher
    Nature Research
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1038/s42003-020-1033-y
    Abstract
    Melanoma represents the most serious type of skin cancer. Although recent years have seen advances using targeted and immunotherapies, most patients remain at high risk for tumor recurrence. Here we show that IRAK-M, a negative regulator of MyD88 signaling, is deficient or low in melanoma and expression levels correlate with patient survival. Inducing IRAK-M expression using genetic approaches or epigenetic modifiers initiates apoptosis by prompting its interaction with TRAF6 via IRAK-M's C-terminal domain. This complex recruits and degrades calpastatin which stimulates calpain activity and triggers caspase-3-dependent but caspase-8,-9-independent apoptosis. Using a drug screen, we identified compounds that induced IRAK-M expression. Administration of IRAK-M-inducing drugs reduced tumor growth in mice but was ineffective against IRAK-M knock-down tumors. These results uncover a previously uncharacterized apoptosis pathway, emphasize IRAK-M as a potential therapeutic target and suggest that the anticancer activity of certain drugs could do so through their ability to induce IRAK-M expression. Copyright 2020, The Author(s).
    Sponsors
    This work was supported by the US Department of Veteran Affair Merit Award 1I01BX002142, National Cancer Institute R01CA207913, the University of Maryland Greenebaum Comprehensive Cancer Center, and the University of Colorado Comprehensive Cancer Center.
    Keyword
    IRAK-M expression
    calpastatin
    Melanoma
    Apoptosis
    TNF Receptor-Associated Factor 6
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85086330329&doi=10.1038%2fs42003-020-1033-y&partnerID=40&md5=43b395cd8f051be614e1069bccba796d; http://hdl.handle.net/10713/13121
    ae974a485f413a2113503eed53cd6c53
    10.1038/s42003-020-1033-y
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