Melatonin inhibits MLL-rearranged leukemia via RBFOX3/hTERT and NF-κB/COX-2 signaling pathways
Melatonin inhibits MLL-rearranged leukemia via RBFOX3/hTERT and NF-κB/COX-2 signaling pathways
复制标题
Melatonin 通过 RBFOX3/hTERT 和 NF-kappaB/COX-2 信号通路抑制 MLL 重排白血病。
DOI：
10.1016/j.canlet.2018.11.037
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发表时间：
2019-01-01
期刊：
影响因子：
9.7
通讯作者：
Deng, Wuguo
中科院分区：
文献类型：
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作者：
Tang, Yan-Lai;Sun, Xi;Deng, Wuguo
MLL重排白血病是一种侵袭性恶性肿瘤，预后差，常规治疗难以治愈。褪黑激素已被证明具有抗肿瘤活性，但褪黑激素对MLL-r白血病的作用及其机制仍知之甚少。在这项研究中，褪黑激素抑制细胞增殖，并通过激活半胱天冬酶依赖的凋亡途径诱导MLL-R白血病细胞凋亡。机制研究表明，褪黑激素通过废除RBFOX 3的hTERT启动子的结合活性抑制hTERT的表达。褪黑激素还阻断NF-κ B核转位并抑制NP-κ B与考克斯-2启动子的结合，从而抑制考克斯-2的表达。此外，临床样品显示褪黑激素在离体的原代MLL-r白血病母细胞中发挥抗白血病活性。在体内，在MLL-r白血病异种移植小鼠模型中，用褪黑激素治疗的小鼠经历了比对照组更大的白血病负荷减少。总的来说，这些结果表明褪黑激素通过抑制RBFOX 3/hTERT和NF-κ B/考克斯-2信号通路来抑制MLL重排白血病。我们的研究结果为褪黑激素在MLL-r白血病治疗中的作用提供了新的见解。
MLL-rearranged leukemia is an aggressive malignancy associated with poor outcome, which is refractory to conventional treatment. Melatonin has been proven to exert anti-tumor activity, but the effect of melatonin on MLL-r leukemia and the underlying mechanism remain poorly understood. In this study, melatonin inhibited cell proliferation and induced apoptosis by activating the caspase-dependent apoptotic pathway in MLL-r leukemia cells. Mechanistic investigations revealed that melatonin suppressed the expression of hTERT by abrogating the binding activity of RBFOX3 to the hTERT promoter. Melatonin also blocked NF-kappa B nuclear translocation and suppressed NP-kappa B binding to the COX-2 promoter, thereby suppressing the expression of COX-2. In addition, clinical samples revealed that melatonin exerts anti-leukemic activity in primary MLL-r leukemia blasts ex vivo. In vivo, the mice treated with melatonin experienced a larger reduction in leukemic burden than the control group in a MLL-r leukemia xenograft mouse model. Collectively, these results suggest that melatonin inhibits MLL-rearranged leukemia through suppressing the RBFOX3/hTERT and NF-kappa B/COX-2 signaling pathways. Our findings provide new insights into the role of melatonin for MLL-r leukemia treatment.