ABT-263-induced MCL1 upregulation depends on autophagy-mediated 4EBP1 downregulation in human leukemia cells

作者：Lee, Yuan Chin; Wang, Liang Jun; Huang, Chia Hui; Shi, Yi Jun; Chang, Long Sen^*

来源：Cancer Letters, 2018, 432: 191-204.

DOI：10.1016/j.canlet.2018.06.019

• BH3 mimetic
• MCL1 protein synthesis
• 4EBP1 mRNA stability
• NF kappa B-modulated autophagy
• Amsacrine

The present study aimed to investigate the pathway related to MCL1 expression in ABT-263-treated human leukemia U937 cells. ABT-263 upregulated MCL1 protein expression but did not affect its mRNA level and protein stability. Notably, ABT-263 increased 4EBP1 mRNA decay and thus reduced 4EBP1 expression. Overexpression of 4EBP1 abrogated ABT-263-induced MCL1 upregulation. ABT-263-induced activation of IKK alpha/beta-NF kappa B axis elicited autophagy of U937 cells, leading to reduced mRNA stability of 4EBP1. Inhibition of the IKK alpha/beta-NF kappa B axis or autophagy mitigated the effect of ABT-263 on 4EBP1 and MCL1 expression. Amsacrine enhanced the cytotoxicity of ABT-263 in human leukemia U937, HL-60, and Jurkat cells because of its inhibitory effect on the IKK alpha/beta-NF kappa B-mediated pathway. Our data indicate that ABT-263 alleviates the inhibitory effect of 4EBP1 on MCL1 protein synthesis through IKK alpha/beta-NF kappa B-mediated induction of autophagy, and suggest a promising strategy to improve anti-leukemia therapy with ABT-263.

• 出版日期2018
• 单位中山大学