Journal
CANCER CELL
Volume 29, Issue 2, Pages 145-158Publisher
CELL PRESS
DOI: 10.1016/j.ccell.2016.01.006
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Funding
- NHMRC [1016647, 461221, 1016701, 1025594, 1046984, 1046010, 1025239, 637367, 1008131, 1081221, 1051235, 1057905, 541901, 1058190, 1020136]
- Cancer Council Victoria
- Association pour la Recherche sur le Cancer (ARC)
- Peter Muller fellowship
- Australian Cancer Research Fund
- Victorian State Government Operational Infrastructure Support
- NHMRC IRIISS grant [361646]
- Deutsche Forschungsgemeinschaft [SFB566]
- SNSF project [310030-138085]
- Swiss National Science Foundation (SNF) [310030_138085] Funding Source: Swiss National Science Foundation (SNF)
- National Health and Medical Research Council of Australia [1081221, 1058190, 1057905] Funding Source: NHMRC
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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.
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