2. Academic Validation
  3. Amsacrine downregulates BCL2L1 expression and triggers apoptosis in human chronic myeloid leukemia cells through the SIDT2/NOX4/ERK/HuR pathway

Amsacrine downregulates BCL2L1 expression and triggers apoptosis in human chronic myeloid leukemia cells through the SIDT2/NOX4/ERK/HuR pathway

  • Toxicol Appl Pharmacol. 2023 Jul 12;116625. doi: 10.1016/j.taap.2023.116625.
Yuan-Chin Lee 1,  Jing-Ting Chiou 1,  Liang-Jun Wang 1,  Ying-Jung Chen 2,  Long-Sen Chang 3
Affiliations

Affiliations

  • 1 Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
  • 2 Department of Fragrance and Cosmetic Science, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
  • 3 Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan; Department of Biotechnology, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address: [email protected].
PMID: 37451322 DOI: 10.1016/j.taap.2023.116625
Abstract

Accumulating evidence indicates that the Anticancer activity of acridine derivatives is mediated through the regulation of anti-apoptotic and pro-apoptotic BCL2 protein expression. Therefore, we investigated whether the cytotoxicity of amsacrine with an acridine structural scaffold in human chronic myeloid leukemia (CML) K562 cells was mediated by BCL2 family proteins. Amsacrine induced Apoptosis, mitochondrial depolarization, and BCL2L1 (also known as Bcl-xL) downregulation in K562 cells. BCL2L1 overexpression inhibited amsacrine-induced cell death and mitochondrial depolarization. Amsacrine treatment triggered SIDT2-mediated miR-25 downregulation, leading to increased NOX4-mediated ROS production. ROS-mediated inactivation of ERK triggered miR-22 expression, leading to increased HuR mRNA decay. As HuR is involved in stabilizing BCL2L1 mRNA, downregulation of BCL2L1 was noted in K562 cells after amsacrine treatment. In contrast, amsacrine-induced BCL2L1 downregulation was alleviated by restoring ERK phosphorylation and HuR expression. Altogether, the results of this study suggest that amsacrine triggers Apoptosis in K562 cells by inhibiting BCL2L1 expression through the SIDT2/NOX4/ERK-mediated downregulation of HuR. Furthermore, a similar pathway also explains the cytotoxicity of amsacrine in CML MEG-01 and KU812 cells.

Keywords

Amsacrine; BCL2L1; Chronic myeloid leukemia; ERK; HuR; NOX4.

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