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ABSTRACT Objectives Methods Results Conclusion 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.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.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.GSK‐3β functions as an oncogene in ATL and could be a potential therapeutic target. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to determine the role of dihydroorotate dehydrogenase (DHODH) in pathogenesis of adult T‐cell leukemia (ATL) caused by human T‐cell leukemia virus type 1 (HTLV‐1) and the effects of its inhibition on the de novo pyrimidine biosynthesis pathway. Methods: Cell proliferation, viability, cycle, and apoptosis were analyzed using WST‐8 assays, flow cytometry, and Hoechst 33342 staining. To elucidate the molecular mechanisms involved in the anti‐ATL effects of DHODH knockdown and inhibition, RT‐PCR and immunoblotting were conducted. Results: HTLV‐1‐infected T‐cell lines aberrantly expressed DHODH. Viral infection and the oncoprotein, Tax, enhanced DHODH expression, while knockdown of DHODH decreased HTLV‐1‐infected T‐cell growth. In addition, BAY2402234, a DHODH inhibitor, exerted an anti‐proliferative effect, which was reversed by uridine supplementation. BAY2402234 induced DNA damage and S phase arrest by downregulating c‐Myc, CDK2, and cyclin A and upregulating p53 and cyclin E. It also induced caspase‐mediated apoptosis by the upregulation of pro‐apoptotic and downregulation of anti‐apoptotic proteins. Furthermore, BAY2402234 induced caspase‐independent ferroptosis and necroptosis. It decreased phosphorylation of IKK, IκBα, PTEN, Akt, and its downstream targets, suggesting that inhibition of NF‐κB and Akt signaling is involved in its anti‐ATL action. Conclusion: These findings highlight DHODH as a potential therapeutic target for treating ATL. [ABSTRACT FROM AUTHOR]