Naslov
The ribonucleoside AICAr induces monocytic differentiation via pyrimidine depletion

Autori
Dembitz, Vilma ; Tomić, Barbara ; Kodvanj, Ivan ; Višnjić, Dora

Vrsta, podvrsta i kategorija rada
Sažeci sa skupova, sažetak, ostalo

Skup
Annual meeting of the Croatian Immunological Society 2019

Mjesto i datum
Rovinj, Hrvatska, 11.10.2019. - 12.10.2019

Vrsta sudjelovanja
Poster

Vrsta recenzije
Podatak o recenziji nije dostupan

Ključne riječi
AMl, AICAr, differentiation, pyrimidines

Sažetak
Changes in metabolic pathways have been shown to regulate myeloid differentiation both in physiologic and pathologic conditions. Our previous work demonstrated that 5-aminoimidazole- 4- carboxamide ribonucleoside (AICAr), a commonly used AMP-activated kinase (AMPK) modulator, induced monocytic differentiation in U937 monocytic leukemia cell line in an AMPK- independent manner. The aim of this study was to determine the metabolic pathways necessary for AICArmediated differentiation. Here, using metabolic assays, flow cytometry and LC/MS/MS analyses we showed that AICAr-mediated differentiation was independent of the known metabolic effects of AMPK, including glycolysis, but instead depended on glutamine metabolism and pyrimidine synthesis. The addition of nucleosides or uridine alone completely abolished AICAr-induced differentiation and arrest of U937 cells in the S- phase of the cell cycle. LC/MS/MS analysis revealed that AICAr increased the level of orotate and decreased the level of uridine monophosphate (UMP) consistent with inhibition of UMP synthesis, at a step downstream of dihydroorotate dehydrogenase (DHODH). Low concentrations of AICAr and brequinar, an inhibitor of DHODH, had synergistic effects on differentiation and S-phase arrest. Similar effects of AICAr were observed in other cell lines, including monocytic MOLM-14 and THP-1, where they were also uridine dependent. In conclusion, AICAr induces differentiation via inhibition of UMP-synthesis and pyrimidine depletion.

Izvorni jezik
Engleski

POVEZANOST RADA