The ribonucleoside AICAr induces differentiation of myeloid leukemia by activating the ATR/Chk1 kinase via pyrimidine depletion (CROSBI ID 270182)
Prilog u časopisu | izvorni znanstveni rad | međunarodna recenzija
Podaci o odgovornosti
Dembitz, Vilma ; Tomić, Barbara ; Kodvanj, Ivan ; Simon, Julian ; Bedalov, Antonio ; Visnjic, Dora
engleski
The ribonucleoside AICAr induces differentiation of myeloid leukemia by activating the ATR/Chk1 kinase via pyrimidine depletion
Metabolic pathways play important roles in proliferation and differentiation of malignant cells. 5-Aminoimidazole-4-carboxamide ribonucleoside (AICAr), a precursor in purine biosynthesis and a well-established activator of AMP-activated protein kinase (AMPK), induces widespread metabolic alterations and is commonly used for dissecting the role of metabolism in cancer. We have previously reported that AICAr promotes differentiation and inhibits proliferation of myeloid leukemia cells. Here, using metabolic assays, immunoblotting, flow cytometry analyses, and siRNA-mediated gene silencing in leukemia cell lines, we show that AICAr-mediated differentiation was independent of the known metabolic effects of AMPK, including glucose consumption, but instead depends on the activation of the DNA damage-associated enzyme checkpoint kinase 1 (Chk1) induced by pyrimidine depletion. LC/MS/MS metabolomics analysis revealed that AICAr increases orotate levels and decreases uridine monophosphate (UMP) levels, consistent with inhibition of UMP synthesis at a step downstream of dihydroorotate dehydrogenase (DHODH). AICAr and the DHODH inhibitor brequinar had similar effects on differentiation markers and S-phase arrest, and genetic or pharmacological Chk1 inactivation abrogated both of these effects. Our results delineate an AMPK-independent effect of AICAr on myeloid leukemia differentiation that involves perturbation of pyrimidine biosynthesis and activation of the DNA damage response network.
AICAr ; Chk1 ; AML ; leukemia ; cell differentiation ; DNA damage response ; AMP-activated kinase (AMPK) ; nucleotide cell ; cycle pyrimidine
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Podaci o izdanju
294 (42)
2019.
15257-15270
objavljeno
0021-9258
1083-351X
10.1074/jbc.RA119.009396
Trošak objave rada u otvorenom pristupu
Povezanost rada
Temeljne medicinske znanosti