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Viability of diffuse large B-cell lymphoma cells is regulated by kynurenine 3-monooxygenase activity

Diffuse large B-cell lymphoma (DLBCL) is a clinically heterogeneous lymphoid malignancy that is the most common type of lymphoma in Japan. Previous studies have demonstrated that patients with DLBCL have a poor prognosis due to increased levels of indoleamine 2,3-dioxygnase and kynurenine (KYN). How...

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Detalles Bibliográficos
Autores principales: Morita, Nanaka, Hoshi, Masato, Hara, Takeshi, Ninomiya, Soranobu, Enoki, Taisuke, Yoneda, Misao, Tsurumi, Hisashi, Saito, Kuniaki
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461759/
https://www.ncbi.nlm.nih.gov/pubmed/34584567
http://dx.doi.org/10.3892/ol.2021.13051
Descripción
Sumario:Diffuse large B-cell lymphoma (DLBCL) is a clinically heterogeneous lymphoid malignancy that is the most common type of lymphoma in Japan. Previous studies have demonstrated that patients with DLBCL have a poor prognosis due to increased levels of indoleamine 2,3-dioxygnase and kynurenine (KYN). However, the roles of metabolites acting downstream of KYN and associated enzymes are not fully understood. The present study investigated the role of kynurenine 3-monooxygenase (KMO), which catalyzes the conversion of KYN to 3-hydroxykynurenine (3-HK), using serum samples from patients with DLBCL and human DLBCL cell lines with different KMO expression [STR-428 cells with high levels of KMO expression (KMO(high)) and KML-1 cells with low levels of KMO expression (KMO(low))]. Serum samples from 28 patients with DLBCL and 34 healthy volunteers were used to investigate the association between prognosis and KMO activity or 3-HK levels. Furthermore, to investigate the roles of KMO and its related metabolites, STR-428 and KML-1 cell lines, and the lymph nodes of patients with DLBCL were analyzed by reverse transcription-quantitative PCR for KMO, KYNU, 3-hydroxyanthranilate-3,4-dioxygenase and quinolinate phosphoribosyltransferase, by western blotting, and immunohistochemical or immunofluorescence staining for KMO, and by cell viability and NAD(+)/NADH assays. KYN pathway metabolites in serum samples were measured by HPLC. Serum 3-HK levels were regulated independently of serum KYN levels, and increased serum 3-HK levels and KMO activity were found to be associated with worse disease progression. Notably, the addition of KMO inhibitors and 3-HK negatively and positively regulated the viability of DLBCL cells, respectively. Furthermore, NAD(+) levels in KMO(high) STR-428 cells were significantly higher than those in KMO(low) KML-1 cells. These results suggested that 3-HK generated by KMO activity may be involved in the regulation of DLBCL cell viability via NAD(+) synthesis.