TAK1 inhibition subverts the osteoclastogenic action of TRAIL while potentiating its antimyeloma effects
TAK1 inhibition subverts the osteoclastogenic action of TRAIL while potentiating its antimyeloma effects
复制标题
DOI：
10.1182/bloodadvances.2017008813
复制
发表时间：
2017-11-14
期刊：
影响因子：
7.5
通讯作者：
Abe, Masahiro
中科院分区：
文献类型：
--
作者：
Tenshin, Hirofumi;Teramachi, Jumpei;Abe, Masahiro
肿瘤坏死因子相关凋亡诱导配体（TRAIL）激动剂诱导肿瘤特异性凋亡，表明它们可能是一种有吸引力的治疗癌症，包括多发性骨髓瘤（MM）的策略。破骨细胞生成在MM中被高度诱导，这反过来又促进MM生长，从而在MM肿瘤扩张和骨破坏之间形成恶性循环。然而，TRAIL对MM增强的破骨细胞生成的影响在很大程度上仍然未知。在此，我们发现TRAIL诱导MM细胞凋亡，但不诱导破骨细胞（OC）凋亡，而且它促进NF-κ B B配体受体激活剂诱导的破骨细胞生成沿着细胞FLICE抑制蛋白（c-FLIP）的上调。TRAIL在OC中不诱导死亡诱导信号复合物的形成，但与转化生长因子β激活的激酶1（TAK 1）的磷酸化形成次级复合物（复合物II），从而激活NF-β B信号。c-FLIP敲除消除复合物II的形成，从而允许TRAIL诱导OC细胞死亡。TAK 1抑制剂LLZ 1640 -2消除了TRAIL诱导的c-FLIP上调和NF-κ B激活，并触发了TRAIL诱导的caspase-8激活和OC中的细胞死亡。有趣的是，TRAIL诱导的caspase-8活化导致转录因子Sp1的酶降解，从而显著降低c-FLIP表达，这进一步使OC对TRAIL诱导的凋亡敏感。此外，TAK 1抑制诱导抗破骨细胞活性的TRAIL，即使在与MM细胞的共培养，同时加强TRAIL的抗MM效果。这些结果表明，成骨细胞谱系细胞通过使caspase-8依赖性凋亡倾向于NF-κ B活化而使用TRAIL进行分化和活化，并且TAK 1抑制破坏了TRAIL介导的NF-κ B活化以恢复OC中的TRAIL诱导的凋亡，同时与TRAIL组合进一步增强MM细胞死亡。
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) agonists induce tumorspecific apoptosis indicating that they may be an attractive therapeutic strategy against cancers, including multiple myeloma (MM). Osteoclastogenesis is highly induced in MM, which in turn enhances MM growth, thereby forming a vicious cycle between MM tumor expansion and bone destruction. However, the effects of TRAIL on MM-enhanced osteoclastogenesis remain largely unknown. Here, we show that TRAIL induced apoptosis in MM cells, but not in osteoclasts (OCs), and that it rather facilitated receptor activator of NF-kappa B ligand-induced osteoclastogenesis along with upregulation of cellular FLICE inhibitory protein (c-FLIP). TRAIL did not induce death-inducing signaling complex formation in OCs, but formed secondary complex (complex II) with the phosphorylation of transforming growth factor beta-activated kinase-1 (TAK1), and thus activated NF-beta B signaling. c-FLIP knockdown abolished complex II formation, thus permitting TRAIL induction of OC cell death. The TAK1 inhibitor LLZ1640-2 abrogated the TRAIL-induced c-FLIP upregulation and NF-kappa B activation, and triggered TRAIL-induced caspase-8 activation and cell death in OCs. Interestingly, the TRAIL-induced caspase-8 activation caused enzymatic degradation of the transcription factor Sp1 to noticeably reduce c-FLIP expression, which further sensitized OCs to TRAIL-induced apoptosis. Furthermore, the TAK1 inhibition induced antiosteoclastogenic activity by TRAIL even in cocultures with MM cells while potentiating TRAIL's anti-MM effects. These results demonstrated that osteoclastic lineage cells use TRAIL for their differentiation and activation through tilting caspase-8-dependent apoptosis toward NF-kappa B activation, and that TAK1 inhibition subverts TRAIL-mediated NF-kB activation to resume TRAIL-induced apoptosis in OCs while further enhancing MM cell death in combination with TRAIL.