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The ribonucleoside AICAr induces differentiation of myeloid leukemia by activating the ATR/Chk1 via pyrimidine depletion.

Authors
  • Dembitz, Vilma1
  • Tomic, Barbara1
  • Kodvanj, Ivan1
  • Simon, Julian A2
  • Bedalov, Antonio2
  • Visnjic, Dora3
  • 1 Department of Physiology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia. , (Croatia)
  • 2 Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109.
  • 3 Department of Physiology and Croatian Institute for Brain Research, School of Medicine, University of Zagreb, 10 000 Zagreb, Croatia [email protected] , (Croatia)
Type
Published Article
Journal
Journal of Biological Chemistry
Publisher
American Society for Biochemistry and Molecular Biology
Publication Date
Oct 18, 2019
Volume
294
Issue
42
Pages
15257–15270
Identifiers
DOI: 10.1074/jbc.RA119.009396
PMID: 31431503
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. © 2019 Dembitz et al.

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