Induction of IRAK-M in melanoma induces caspase-3 dependent apoptosis by reducing TRAF6 and calpastatin levels
Date
2020Journal
Communications BiologyPublisher
Nature ResearchType
Article
Metadata
Show full item recordAbstract
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.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/10713/13121ae974a485f413a2113503eed53cd6c53
10.1038/s42003-020-1033-y
Scopus Count
Collections
Related articles
- The structure function of the death domain of human IRAK-M.
- Authors: Du J, Nicolaes GA, Kruijswijk D, Versloot M, van der Poll T, van 't Veer C
- Issue date: 2014 Dec 7
- IRAK-1-mediated negative regulation of Toll-like receptor signaling through proteasome-dependent downregulation of TRAF6.
- Authors: Muroi M, Tanamoto K
- Issue date: 2012 Feb
- TRAF6 distinctively mediates MyD88- and IRAK-1-induced activation of NF-kappaB.
- Authors: Muroi M, Tanamoto K
- Issue date: 2008 Mar
- Identification of TIFA as an adapter protein that links tumor necrosis factor receptor-associated factor 6 (TRAF6) to interleukin-1 (IL-1) receptor-associated kinase-1 (IRAK-1) in IL-1 receptor signaling.
- Authors: Takatsuna H, Kato H, Gohda J, Akiyama T, Moriya A, Okamoto Y, Yamagata Y, Otsuka M, Umezawa K, Semba K, Inoue J
- Issue date: 2003 Apr 4
- TGF-β-induced IRAK-M expression in tumor-associated macrophages regulates lung tumor growth.
- Authors: Standiford TJ, Kuick R, Bhan U, Chen J, Newstead M, Keshamouni VG
- Issue date: 2011 May 26