| Literature DB >> 26859455 |
Najoua Lalaoui1, Kay Hänggi2, Gabriela Brumatti1, Diep Chau1, Nhu-Y N Nguyen3, Lazaros Vasilikos2, Lisanne M Spilgies2, Denise A Heckmann1, Chunyan Ma1, Margherita Ghisi4, Jessica M Salmon4, Geoffrey M Matthews4, Elisha de Valle5, Donia M Moujalled3, Manoj B Menon6, Sukhdeep Kaur Spall1, Stefan P Glaser1, Jennifer Richmond7, Richard B Lock7, Stephen M Condon8, Raffi Gugasyan5, Matthias Gaestel6, Mark Guthridge3, Ricky W Johnstone4, Lenka Munoz9, Andrew Wei3, Paul G Ekert10, David L Vaux1, W Wei-Lynn Wong2, John Silke11.
Abstract
Birinapant is a smac-mimetic (SM) in clinical trials for treating cancer. SM antagonize inhibitor of apoptosis (IAP) proteins and simultaneously induce tumor necrosis factor (TNF) secretion to render cancers sensitive to TNF-induced killing. To enhance SM efficacy, we screened kinase inhibitors for their ability to increase TNF production of SM-treated cells. We showed that p38 inhibitors increased TNF induced by SM. Unexpectedly, even though p38 is required for Toll-like receptors to induce TNF, loss of p38 or its downstream kinase MK2 increased induction of TNF by SM. Hence, we show that the p38/MK2 axis can inhibit or promote TNF production, depending on the stimulus. Importantly, clinical p38 inhibitors overcame resistance of primary acute myeloid leukemia to birinapant.Entities:
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Year: 2016 PMID： 26859455 DOI： 10.1016/j.ccell.2016.01.006
Source DB: PubMed Journal: Cancer Cell ISSN： 1535-6108 Impact factor: 31.743