1. Academic Validation
  2. Arsenic trioxide-induced p38 MAPK and Akt mediated MCL1 downregulation causes apoptosis of BCR-ABL1-positive leukemia cells

Arsenic trioxide-induced p38 MAPK and Akt mediated MCL1 downregulation causes apoptosis of BCR-ABL1-positive leukemia cells

  • Toxicol Appl Pharmacol. 2020 Apr 17;397:115013. doi: 10.1016/j.taap.2020.115013.
Chia-Hui Huang 1 Yuan-Chin Lee 1 Jing-Ting Chiou 1 Yi-Jun Shi 1 Liang-Jun Wang 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

In this study, we investigated the mechanisms underlying arsenic trioxide (ATO)-induced death of human BCR-ABL1-positive K562 and MEG-01 cells. ATO-induced apoptotic death in K562 cells was characterized by ROS-mediated mitochondrial depolarization, MCL1 downregulation, p38 MAPK activation, and Akt inactivation. ATO-induced BCR-ABL1 downregulation caused Akt inactivation but not p38 MAPK activation. Akt inactivation increased GSK3β-mediated MCL1 degradation, while p38 MAPK-mediated NFκB activation coordinated with HDAC1 suppressed MCL1 transcription. Inhibition of p38 MAPK activation or overexpression of constitutively active Akt increased MCL1 expression and promoted the survival of ATO-treated cells. Overexpression of MCL1 alleviated mitochondrial depolarization and cell death induced by ATO. The same pathway was found to be involved in ATO-induced death in MEG-01 cells. Remarkably, YM155 synergistically enhanced the cytotoxicity of ATO on K562 and MEG-01 cells through suppression of MCL1 and Survivin. Collectively, our data indicate that ATO-induced p38 MAPK- and Akt-mediated MCL1 downregulation triggers Apoptosis in K562 and MEG-01 cells, and that p38 MAPK activation is independent of ATO-induced BCR-ABL1 suppression.

Keywords

Akt-controlled MCL1 degradation; Arsenic trioxide; Leukemia; p38 MAPK-modulated MCL1 transcription.

Figures
Products