Disruption of Nucleotide Homeostasis by the Antiproliferative Drug 5-Aminoimidazole-4-carboxamide-1-β-d-ribofuranoside Monophosphate (AICAR).
5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside monophosphate (AICAR) is a natural metabolite with potent anti-proliferative and low energy mimetic properties. At high concentration, AICAR is toxic for yeast and mammalian cells, but the molecular basis of this toxicity is poorly understood. Here, we report the identification of yeast purine salvage pathway mutants that are synthetically lethal with AICAR accumulation. Genetic suppression revealed that this synthetic lethality is in part due to low expression of adenine phosphoribosyl transferase under high AICAR conditions. In addition, metabolite profiling points to the AICAR/NTP balance as crucial for optimal utilization of glucose as a carbon source. Indeed, we found that AICAR toxicity in yeast and human cells is alleviated when glucose is replaced by an alternative carbon source. Together, our metabolic analyses unveil the AICAR/NTP balance as a major factor of AICAR antiproliferative effects.
From the Université de Bordeaux and the Centre National de la Recherche Scientifique, Institut de Biochimie et Génétique Cellulaires UMR 5095, Saint-Saëns, F-33077 Bordeaux, France.
Johanna
J
Ceschin
From the Université de Bordeaux and the Centre National de la Recherche Scientifique, Institut de Biochimie et Génétique Cellulaires UMR 5095, Saint-Saëns, F-33077 Bordeaux, France.
Hans Caspar
HC
Hürlimann
From the Université de Bordeaux and the Centre National de la Recherche Scientifique, Institut de Biochimie et Génétique Cellulaires UMR 5095, Saint-Saëns, F-33077 Bordeaux, France.
Christelle
C
Saint-Marc
From the Université de Bordeaux and the Centre National de la Recherche Scientifique, Institut de Biochimie et Génétique Cellulaires UMR 5095, Saint-Saëns, F-33077 Bordeaux, France.
Delphine
D
Albrecht
From the Université de Bordeaux and the Centre National de la Recherche Scientifique, Institut de Biochimie et Génétique Cellulaires UMR 5095, Saint-Saëns, F-33077 Bordeaux, France.
Typhaine
T
Violo
From the Université de Bordeaux and the Centre National de la Recherche Scientifique, Institut de Biochimie et Génétique Cellulaires UMR 5095, Saint-Saëns, F-33077 Bordeaux, France.
Michel
M
Moenner
From the Université de Bordeaux and the Centre National de la Recherche Scientifique, Institut de Biochimie et Génétique Cellulaires UMR 5095, Saint-Saëns, F-33077 Bordeaux, France b.daignan-fornier@ibgc.cnrs.fr.
Bertrand
B
Daignan-Fornier
From the Université de Bordeaux and the Centre National de la Recherche Scientifique, Institut de Biochimie et Génétique Cellulaires UMR 5095, Saint-Saëns, F-33077 Bordeaux, France.
Benoît
B
Pinson
D000228:Adenine Phosphoribosyltransferase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D009711:Nucleotides / Q000235:genetics / Q000378:metabolism*; D012265:Ribonucleotides / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
D009711:Nucleotides; D012265:Ribonucleotides; D029701:Saccharomyces cerevisiae Proteins; D000620:Aminoimidazole Carboxamide; D000228:Adenine Phosphoribosyltransferase; C031143:AICA ribonucleotide
nucleoside/nucleotide analog; nucleoside/nucleotide metabolism; purine; yeast genetics; yeast metabolism