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

• 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
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2018.11.037

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.