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  2. CREB/Sp1-mediated MCL1 expression and NFκB-mediated ABCB1 expression modulate the cytotoxicity of daunorubicin in chronic myeloid leukemia cells

CREB/Sp1-mediated MCL1 expression and NFκB-mediated ABCB1 expression modulate the cytotoxicity of daunorubicin in chronic myeloid leukemia cells

  • Toxicol Appl Pharmacol. 2022 Jan 15;435:115847. doi: 10.1016/j.taap.2021.115847.
Jing-Ting Chiou 1 Chia-Hui Huang 1 Ti-Hsiao Wu 2 Liang-Jun Wang 1 Yuan-Chin Lee 1 Po-Wei Huang 3 Long-Sen Chang 4
Affiliations

Affiliations

  • 1 Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
  • 2 Department of Cardiovascular Surgery, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung 813, Taiwan.
  • 3 Department of Surgery, Zuoying Branch of Kaohsiung Armed Forces General Hospital, Kaohsiung 813, Taiwan.
  • 4 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

Although some studies have hinted at the therapeutic potential of daunorubicin (DNR) in chronic myeloid leukemia (CML), the mechanism by which DNR induces CML cell death is unclear. Therefore, this study aimed to investigate DNR-induced cell death signaling pathways in CML cell lines K562 and KU812. DNR-triggered Apoptosis in K562 cells was characterized by inhibition of MCL1 expression, while restoration of MCL1 expression protected K562 cells from DNR-mediated cytotoxicity. In addition, DNR induced NOX4-dependent ROS production, leading to the activation of p38 MAPK and inactivation of Akt and ERK. Activated p38 MAPK stimulated protein Phosphatase 2A-dependent dephosphorylation of CREB. Since Akt-mediated activation of ERK reduced β-TrCP mRNA stability, the inactivation of Akt-ERK axis increased β-TrCP expression, which in turn promoted proteasomal degradation of Sp1. Inhibition of CREB phosphorylation and Sp1 expression simultaneously reduced MCL1 transcription and protein expression. DNR-induced MCL1 suppression was not reliant on its ability to induce DNA damage. In addition, DNR induced the expression of drug exporter ABCB1 in K562 cells through the p38 MAPK/NFκB-mediated pathway, while imatinib or ABT-199 inhibited the DNR-induced effect. The combination of imatinib or ABT-199 with DNR showed synergistic cytotoxicity in K562 cells by increasing intracellular DNR retention. Cumulatively, our data indicate that DNR induces MCL1 downregulation in K562 cells by promoting p38 MAPK-mediated dephosphorylation of CREB and inhibiting the Akt-ERK axis-mediated Sp1 protein stabilization. Furthermore, experimental evidence indicates that DNR-induced death of KU812 cells occurs through a similar pathway.

Keywords

CREB/Sp1-mediated MCL1 expression; Daunorubicin; Leukemia; NFκB-mediated ABCB1 expression; p38 MAPK/PP2A axis: Akt/ERK/β-TrCP axis.

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