1. Academic Validation
  2. Cytarabine-induced destabilization of MCL1 mRNA and protein triggers apoptosis in leukemia cells

Cytarabine-induced destabilization of MCL1 mRNA and protein triggers apoptosis in leukemia cells

  • Biochem Pharmacol. 2023 Mar 14;115494. doi: 10.1016/j.bcp.2023.115494.
Jing-Ting Chiou 1 Chia-Chi Hsu 1 Ying-Chung Hong 2 Yuan-Chin Lee 1 Long-Sen Chang 3
Affiliations

Affiliations

  • 1 Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
  • 2 Division of Hematology/Oncology, Department of Medicine, Kaohsiung Veterans General Hospital, Kaohsiung 813, 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].
Abstract

Although cytarabine (Ara-C) is the mainstay of treatment for acute myeloid leukemia (AML), its cytotoxic mechanisms for inducing Apoptosis are poorly understood. Therefore, we investigated the Ara-C-induced cell death pathway in human AML U937 cells. Ara-C-induced downregulation of MCL1 is associated with the induction of mitochondrial depolarization and Apoptosis. Ara-C triggered NOX4-mediated ROS production, which in turn activated p38 MAPK but inactivated Akt. Ara-C-induced DNA damage modulates p38 MAPK activation without affecting Akt inactivation in U937 cells. Inactivated Akt promotes GSK3β-dependent CREB phosphorylation, which in turn increases NOXA transcription, thereby triggering the degradation of MCL1 protein. Activated p38 MAPK induces HuR downregulation, leading to accelerated MCL1 mRNA turnover. A similar pathway also explains the Ara-C-induced THP-1 cell death. Collectively, our data confirm that Ara-C-triggered Apoptosis in the AML cell lines U937 and THP-1 is mediated through the destabilization of MCL1 mRNA and protein. Furthermore, Ara-C acts synergistically with the BCL2 inhibitor ABT-199 to induce cell death in ABT-199-resistant and parental U937 cells by inhibiting MCL1 expression.

Keywords

AKT/GSK3β/CREB axis; Cytarabine; HuR axis; Leukemia; MCL1 downregulation; p38 MAPK.

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