1. Academic Validation
  2. BCL2L1 inhibitor A-1331852 inhibits MCL1 transcription and triggers apoptosis in acute myeloid leukemia cells

BCL2L1 inhibitor A-1331852 inhibits MCL1 transcription and triggers apoptosis in acute myeloid leukemia cells

  • Biochem Pharmacol. 2023 Aug 8;115738. doi: 10.1016/j.bcp.2023.115738.
Jing-Ting Chiou 1 Yu-Ying Wu 1 Yuan-Chin Lee 1 Long-Sen Chang 2
Affiliations

Affiliations

  • 1 Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
  • 2 Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address: lschang@mail.nsysu.edu.tw.
Abstract

BH3 mimetics exert Anticancer activity by inhibiting anti-apoptotic BCL2 proteins. However, accumulating evidence indicates that the off-target effects of these drugs tightly modulates their Anticancer activities. In this study, we investigated whether the BCL2L1 inhibitor A-1331852 induced the death of U937 acute myeloid leukemia (AML) cells through a non-BCL2L1-targeted effect. A-1331852-induced Apoptosis in U937 cells was characterized by increased ROS production, downregulation of MCL1, and loss of mitochondrial membrane potential. Ectopic expression of MCL1 alleviated A-1331852-induced mitochondrial depolarization and cytotoxicity in U937 cells. A-1331852-induced ROS production increased p38 MAPK phosphorylation and inhibited MCL1 transcription. Inhibition of p38 MAPK activation restored MCL1 expression in A-1331852-treated cells. A-1331852 triggered p38 MAPK-mediated Cullin 3 downregulation, which in turn increased PP2Acα expression, thereby reducing CREB phosphorylation. A-1331852 reduced the binding of CREB to the MCL1 promoter, leading to the inhibition of CREB-mediated MCL1 transcription. Furthermore, A-1331852 acted synergistically with the BCL2 inhibitor ABT-199 to induce U937 and ABT-199-resistant U937 cell death by inhibiting MCL1 expression. A similar phenomenon caused A-1331852-induced MCL1 downregulation and cytotoxicity in AML HL-60 cells. Collectively, our data suggest that A-1331852 shows an off-target effect of inhibiting MCL1 transcription, ultimately leading to U937 and HL-60 cell death.

Keywords

A-1331852; Apoptosis; BH3 mimetic; MCL1; Off-target effect.

Figures
Products