Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics
Targeting p38 or MK2 Enhances the Anti-Leukemic Activity of Smac-Mimetics
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DOI：
10.1016/j.ccell.2016.01.006
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发表时间：
2016-02-08
期刊：
影响因子：
50.3
通讯作者：
Silke, John
中科院分区：
文献类型：
--
作者：
Lalaoui, Najoua;Haenggi, Kay;Silke, John
Birinapant是一种用于治疗癌症的临床试验中的smac-mimetic（SM）。SM拮抗细胞凋亡抑制因子（IAP）蛋白，同时诱导肿瘤坏死因子（TNF）分泌，使肿瘤对TNF诱导的杀伤敏感。为了提高SM的功效，我们筛选了激酶抑制剂，以提高SM处理细胞的TNF产生。我们发现p38抑制剂增加SM诱导的TNF。出乎意料的是，尽管Toll样受体诱导TNF需要p38，但p38或其下游激酶MK2的缺失增加了SM对TNF的诱导。因此，我们发现p38/MK2轴可以抑制或促进TNF的产生，这取决于刺激。重要的是，临床p38抑制剂克服了原发性急性髓性白血病对birinapant的耐药性。
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.