A New Strategy for Adult T-Cell Leukemia Treatment Targeting Glycogen Synthase Kinase-3β.

Autor: Ishikawa C; Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.; Division of Health Sciences, Transdisciplinary Research Organization for Subtropics and Island Studies, University of the Ryukyus, Nishihara, Japan., Mori N; Department of Microbiology and Oncology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.
Jazyk: angličtina
Zdroj: European journal of haematology [Eur J Haematol] 2024 Dec; Vol. 113 (6), pp. 852-862. Date of Electronic Publication: 2024 Sep 06.
DOI: 10.1111/ejh.14300
Abstrakt: Objectives: The role of glycogen synthase kinase (GSK)-3β in adult T-cell leukemia (ATL) caused by human T-cell leukemia virus type 1 (HTLV-1) is paradoxical and enigmatic. Here, we investigated the role of GSK-3β and its potential as a therapeutic target for ATL.
Methods: Cell proliferation/survival, cell cycle, apoptosis, and reactive oxygen species (ROS) generation were examined using the WST-8 assay, flow cytometry, and Hoechst 33342 staining, respectively. Expression of GSK-3β and cell cycle/death-related proteins, and survival signals was analyzed using RT-PCR, immunofluorescence staining, and immunoblotting.
Results: HTLV-1-infected T-cell lines showed nuclear accumulation of GSK-3β. GSK-3β knockdown and its inhibition with 9-ING-41 and LY2090314 suppressed cell proliferation/survival. 9-ING-41 induced G2/M arrest by enhancing the expression of γH2AX, p53, p21, and p27, and suppressing the expression of CDK1, cyclin A/B, and c-Myc. It induced caspase-mediated apoptosis by decreasing the expression of Bcl-xL, Mcl-1, XIAP, c-IAP1/2, and survivin, and increasing the expression of Bak and Bax. 9-ING-41 also induced ferroptosis and necroptosis, promoted JNK phosphorylation, and suppressed IKKγ and JunB expression. It inhibited the phosphorylation of IκBα, Akt, and STAT3/5, induced ROS production, and reduced glycolysis-derived lactate levels.
Conclusion: GSK-3β functions as an oncogene in ATL and could be a potential therapeutic target.
(© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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