Pivotal role of dihydroorotate dehydrogenase as a therapeutic target in adult T-cell leukemia.
Eur J Haematol
; 113(1): 99-109, 2024 Jul.
Article
em En
| MEDLINE
| ID: mdl-38558052
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Vírus Linfotrópico T Tipo 1 Humano
/
Leucemia-Linfoma de Células T do Adulto
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Apoptose
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Oxirredutases atuantes sobre Doadores de Grupo CH-CH
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Proliferação de Células
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Di-Hidro-Orotato Desidrogenase
Limite:
Humans
Idioma:
En
Revista:
Eur J Haematol
Assunto da revista:
HEMATOLOGIA
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Japão