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

Abstract

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 IKKα/β-NFκB axis elicited autophagy of U937 cells, leading to reduced mRNA stability of 4EBP1. Inhibition of the IKKα/β-NFκB 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 IKKα/β-NFκB-mediated pathway. Our data indicate that ABT-263 alleviates the inhibitory effect of 4EBP1 on MCL1 protein synthesis through IKKα/β-NFκB-mediated induction of autophagy, and suggest a promising strategy to improve anti-leukemia therapy with ABT-263.

Keywords: 4EBP1 mRNA stability; Amsacrine; BH3 mimetic; MCL1 protein synthesis; NFκB-modulated autophagy.