Melatonin inhibits MLL-rearranged leukemia via RBFOX3/hTERT and NF-κB/COX-2 signaling pathways

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,...

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Bibliographic Details
Published in:Cancer letters 2019-02, Vol.443, p.167-178
Main Authors: Tang, Yan-Lai, Sun, Xi, Huang, Li-Bin, Liu, Xiao-Jian, Qin, Ge, Wang, Li-Na, Zhang, Xiao-Li, Ke, Zhi-Yong, Luo, Jie-Si, Liang, Cong, Peng, Chun-Jin, Tang, Wen-Yan, Li, Yu, Huang, Wenlin, Luo, Xue-Qun, Deng, Wuguo
Format: Article
Language:English
Subjects:
Antitumor agents
Apoptosis
Caspase
Cell growth
Cell proliferation
Cyclooxygenase-2
Drug resistance
Ethics
Experiments
Human telomerase reverse transcriptase
Immunoglobulins
Leukemia
Malignancy
Medical prognosis
Melatonin
Mixed lineage leukemia
NF-κB protein
Nuclear transport
P65
Plasmids
Proliferation
Proteins
Signal transduction
Telomerase reverse transcriptase
Translocation
Xenografts
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Summary: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-κB nuclear translocation and suppressed NF-κB 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-κB/COX-2 signaling pathways. Our findings provide new insights into the role of melatonin for MLL-r leukemia treatment.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2018.11.037