TRAIL-activated stress kinases suppress apoptosis through transcriptional upregulation of MCL-1.
TRAIL-activated stress kinases suppress apoptosis through transcriptional upregulation of MCL-1.
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DOI：
10.1038/cdd.2010.9
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发表时间：
2010-08
影响因子：
12.4
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中科院分区：
文献类型：
--
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肿瘤坏死因子相关的凋亡诱导配体(TRAIL)对肿瘤细胞具有良好的选择性，是一种潜在的抗癌药物。不幸的是，许多癌症表现出或获得了对TRAIL的耐药性。在这项研究中，我们报道TRAIL激活了前列腺癌细胞中的转化生长因子β激活的蛋白激酶1→丝裂原活化蛋白激酶3(MKK3)/MKK6→p38通路，从而在转录水平上上调了抗凋亡的bcl2家族成员mcl1的表达。仅TRAIL一项就引发了“死亡诱导信号复合体”(DISC)的强健形成，启动子caspase-8的激活，以及BH3-Only蛋白BID(TBID)的截断。然而，需要同时破坏p38MAPK通路来抑制MCL-1的表达，从而允许TBID激活促凋亡的bCL-2家族成员BAK，并刺激线粒体外膜通透性(MOMP)。IAP拮抗剂Smac/DIABLO从膜间隙释放足以促进TRAIL诱导的细胞凋亡，而细胞色素c的释放和凋亡体的激活是必不可少的。然而，即使在MOMP之后，线粒体产生的活性氧种(ROS)激活了涉及c-jun氨基末端酶(JNKs)的第二信号通路，类似地上调了MCL-1的表达，并部分挽救了一些细胞的死亡。因此，在线粒体损伤前后，应激蛋白在不同的阶段被激活，通过维持MCL-1的表达来介导TRAIL抵抗。
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a potentially useful anticancer agent with exquisite selectivity for cancer cells. Unfortunately, many cancers show or acquire resistance to TRAIL. In this study we report that TRAIL activates a TGF-β-activated kinase 1→mitogen-activated protein kinase (MAPK) kinase 3 (MKK3)/MKK6→p38 pathway in prostate cancer cells that transcriptionally upregulates expression of the antiapoptotic BCL-2 family member MCL-1. TRAIL alone triggered robust formation of the `death-inducing signaling complex' (DISC), activation of the initiator caspase-8, and truncation of the BH3-only protein BID (tBID). Nevertheless, simultaneous disruption of the p38 MAPK pathway was required to suppress MCL-1 expression, thereby allowing tBID to activate the proapoptotic BCL-2 family member BAK and stimulate mitochondrial outer membrane permeabilization (MOMP). Release of the inhibitor-of-apoptosis (IAP) antagonist, Smac/DIABLO, from the intermembrane space was sufficient to promote TRAIL-induced apoptosis, whereas release of cytochrome c and activation of the apoptosome was dispensable. Even after MOMP, however, mitochondrial-generated reactive oxygen species (ROS) activated a secondary signaling pathway, involving c-Jun N-terminal kinases (JNKs), that similarly upregulated MCL-1 expression and partially rescued some cells from death. Thus, stress kinases activated at distinct steps, before and after mitochondrial injury, mediate TRAIL resistance through maintenance of MCL-1 expression.
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