Melatonin inhibits MLL-rearranged leukemia via RBFOX3/hTERT and NF-κB/COX-2 signaling pathways. (28th February 2019)

• Record Type: Journal Article
• 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
• Is Part Of: Cancer letters. Volume 443(2019)
• Page Start: 167
• Page End: 178
• Publication Date: 2019-02-28
• Subjects: Proliferation -- Apoptosis -- Mixed lineage leukemia -- Human telomerase reverse transcriptase -- P65; MLL-r MLL rearranged -- MLL mixed lineage leukemia -- hTERT human telomerase reverse transcriptase -- RBFOX3 RNA binding protein fox-1 homolog 3; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Electronic journals; 616.994
• DOI: 10.1016/j.canlet.2018.11.037
• Languages: English
• ISSNs: 0304-3835

Abstract

Abstract: 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.