Research Paper Volume 12, Issue 4 pp 3298—3311
Berberine promotes XIAP-mediated cells apoptosis by upregulation of miR-24-3p in acute lymphoblastic leukemia
- 1 Department of Pediatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, People’s Republic of China
received: November 27, 2019 ; accepted: January 22, 2020 ; published: February 13, 2020 ;https://doi.org/10.18632/aging.102813
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Copyright © 2020 Liu et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Background: Berberine (BBR) has gained considerable attention because of its anti-tumor activity. BBR can induce apoptosis of acute lymphoblastic leukemia (ALL) cells through the MDM2/p53 pathway. However, the effects of BBR on those ALL patients with p53 deficiency remain unclear.
Results: We found that BBR reduced ALL cell viability and induced apoptosis in p53-null EU-4 and p53-mutant EU-6 cells by downregulating X-linked inhibitor of apoptosis protein (XIAP), which is increased in ALL tissues and cells. BBR-induced cell apoptosis was attenuated by inhibition of XIAP that was controlled by PIM-2. Mechanistic studies showed that BBR treatment induced an enhancement of miR-24-3p. PIM-2 is a direct target of miR-24-3p. Blockade of PIM-2 or miR-24-3p reversed BBR-induced cell apoptosis. In vivo studies, BBR remarkably alleviated leukemia conditions in a EU4 xenograft mouse model, whereas inhibition of miR-24-3p significantly reversed the effects of BBR in the leukemia condition.
Conclusions: miR-24-3p/PIM-2/XIAP signaling contributes to BBR-mediated leukemia mitigation in p53-defect ALL, which should be further developed as a treatment strategy in ALL patients with p53 deficiency.
Methods: Cell viability and apoptosis were determined using CCK-8 and TUNEL assays, respectively. The dual-luciferase reporter gene system was used to determine the interaction between miR-24-3p and 3′-untranslated regions (UTRs) of PIM-2.
BBR: Berberine; ALL: Acute lymphoblastic leukemia; XIAP: X-linked inhibitor of apoptosis protein; TRAIL: TNF-related apoptosis-inducing ligand; miRNAs: MicroRNAs; UTRs: Untranslated regions; ATCC: American Type Culture Collection; DMEM: Dulbecco's modified Eagle's medium; qRT-PCR: Qualitative Real-Time Polymerase Chain Reaction; ALT: Aminotransferase; AST: Aspartate aminotransferase; WBC: White blood cells; RBC: Red blood cells; HGB: Hemoglobin; CLL: Chronic lymphocytic leukemia; AML: Acute myeloid leukemia.