The NEDD8-activating enzyme inhibitor MLN4924 sensitizes a TNFR1+ subgroup of multiple myeloma cells for TNF-induced cell death.,Cell Death & Disease

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The NEDD8-activating enzyme inhibitor MLN4924 sensitizes a TNFR1+ subgroup of multiple myeloma cells for TNF-induced cell death.
Cell Death & Disease ( IF 8.1 ) Pub Date : 2019-08-13 , DOI: 10.1038/s41419-019-1860-2
Mohamed El-Mesery _{1,

2} , Tina Rosenthal ₂ , Hilka Rauert-Wunderlich _{3,

4} , Martin Schreder ₅ , Thorsten Stühmer ₅ , Ellen Leich ₃ , Andreas Schlosser ₆ , Martin Ehrenschwender ₇ , Harald Wajant ₂ , Daniela Siegmund ₂

Affiliation

The NEDD8-activating enzyme (NAE) inhibitor MLN4924 inhibits cullin-RING ubiquitin ligase complexes including the SKP1-cullin-F-box E3 ligase βTrCP. MLN4924 therefore inhibits also the βTrCP-dependent activation of the classical and the alternative NFĸB pathway. In this work, we found that a subgroup of multiple myeloma cell lines (e.g., RPMI-8226, MM.1S, KMS-12BM) and about half of the primary myeloma samples tested are sensitized to TNF-induced cell death by MLN4924. This correlated with MLN4924-mediated inhibition of TNF-induced activation of the classical NFκB pathway and reduced the efficacy of TNF-induced TNFR1 signaling complex formation. Interestingly, binding studies revealed a straightforward correlation between cell surface TNFR1 expression in multiple myeloma cell lines and their sensitivity for MLN4924/TNF-induced cell death. The cell surface expression levels of TNFR1 in the investigated MM cell lines largely correlated with TNFR1 mRNA expression. This suggests that the variable levels of cell surface expression of TNFR1 in myeloma cell lines are decisive for TNF/MLN4924 sensitivity. Indeed, introduction of TNFR1 into TNFR1-negative TNF/MLN4924-resistant KMS-11BM cells, was sufficient to sensitize this cell line for TNF/MLN4924-induced cell death. Thus, MLN4924 might be especially effective in myeloma patients with TNFR1+ myeloma cells and a TNFhigh tumor microenvironment.

中文翻译：

NEDD8激活酶抑制剂MLN4924使多发性骨髓瘤细胞的TNFR1 +亚组对TNF诱导的细胞死亡敏感。

NEDD8激活酶（NAE）抑制剂MLN4924抑制cullin-ring泛素连接酶复合物，包括SKP1-cullin-F-box E3连接酶βTrCP。因此，MLN4924也抑制了经典和替代性NFĸB途径的βTrCP依赖性激活。在这项工作中，我们发现多个骨髓瘤细胞系的一个亚群（例如RPMI-8226，MM.1S，KMS-12BM）和大约一半的原发性骨髓瘤样品对MLN4924对TNF诱导的细胞死亡敏感。这与MLN4924介导的TNF诱导的经典NFκB途径激活的抑制有关，并降低了TNF诱导的TNFR1信号复合物形成的功效。有趣的是，结合研究揭示了多发性骨髓瘤细胞系中细胞表面TNFR1表达与其对MLN4924 / TNF诱导的细胞死亡的敏感性之间的直接相关性。在研究的MM细胞系中，TNFR1的细胞表面表达水平与TNFR1 mRNA的表达高度相关。这表明骨髓瘤细胞系中TNFR1的细胞表面表达水平的变化对TNF / MLN4924敏感性起决定性作用。实际上，将TNFR1引入TNFR1阴性的TNF / MLN4924抗性KMS-11BM细胞中足以使该细胞系对TNF / MLN4924诱导的细胞死亡敏感。因此，MLN4924在具有TNFR1 +骨髓瘤细胞和TNF高肿瘤微环境的骨髓瘤患者中可能特别有效。将TNFR1引入TNFR1阴性的TNF / MLN4924耐药KMS-11BM细胞中，足以使该细胞系对TNF / MLN4924诱导的细胞死亡敏感。因此，MLN4924在具有TNFR1 +骨髓瘤细胞和TNF高肿瘤微环境的骨髓瘤患者中可能特别有效。将TNFR1引入TNFR1阴性的TNF / MLN4924耐药KMS-11BM细胞中，足以使该细胞系对TNF / MLN4924诱导的细胞死亡敏感。因此，MLN4924在具有TNFR1 +骨髓瘤细胞和TNF高肿瘤微环境的骨髓瘤患者中可能特别有效。

更新日期：2019-08-13

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