Pivotal role of dihydroorotate dehydrogenase as a therapeutic target in adult T‐cell leukemia

Abstract 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.