, Volume 18, Issue 8, pp 1008–1016 | Cite as

AICAR induces Bax/Bak-dependent apoptosis through upregulation of the BH3-only proteins Bim and Noxa in mouse embryonic fibroblasts

  • Diana M. González-Gironès
  • Cristina Moncunill-Massaguer
  • Daniel Iglesias-Serret
  • Ana M. Cosialls
  • Alba Pérez-Perarnau
  • Claudia M. Palmeri
  • Camila Rubio-Patiño
  • Andreas Villunger
  • Gabriel Pons
  • Joan Gil
Original Paper


5-Aminoimidazole-4-carboxamide (AICA) riboside (AICAR) is a nucleoside analogue that is phosphorylated to 5-amino-4-imidazolecarboxamide ribotide (ZMP), which acts as an AMP mimetic and activates AMP-activated protein kinase (AMPK). It has been recently described that AICAR triggers apoptosis in chronic lymphocytic leukemia (CLL) cells, and its mechanism of action is independent of AMPK as well as p53. AICAR-mediated upregulation of the BH3-only proteins BIM and NOXA correlates with apoptosis induction in CLL cells. Here we propose mouse embryonic fibroblasts (MEFs) as a useful model to analyze the mechanism of AICAR-induced apoptosis. ZMP formation was required for AICAR-induced apoptosis, though direct Ampk activation with A-769662 failed to induce apoptosis in MEFs. AICAR potently induced apoptosis in Ampkα1//α2/ MEFs, demonstrating an Ampk-independent mechanism of cell death activation. In addition, AICAR acts independently of p53, as MEFs lacking p53 also underwent apoptosis normally. Notably, MEFs lacking Bax and Bak were completely resistant to AICAR-induced apoptosis, confirming the involvement of the mitochondrial pathway in its mechanism of action. Apoptosis was preceded by ZMP-dependent but Ampk-independent modulation of the mRNA levels of different Bcl-2 family members, including Noxa, Bim and Bcl-2. Bim protein levels were accumulated upon AICAR treatment of MEFs, suggesting its role in the apoptotic process. Strikingly, MEFs lacking both Bim and Noxa displayed high resistance to AICAR. These findings support the notion that MEFs are a useful system to further dissect the mechanism of AICAR-induced apoptosis.


AICAR Ampk Apoptosis Bim Noxa MEFs 



Acetyl-CoA carboxylase


5-Aminoimidazole-4-carboxamide (AICA) riboside or acadesine


AMP-activated protein kinase


Chronic lymphocytic leukemia


Double knockout


Mouse embryonic fibroblasts


Mitochondrial outer membrane permeabilization


Propidium iodide


Reverse transcriptase multiplex ligation-dependent probe amplification


Real time quantitative PCR


Standard error of the mean


Wild type


AICA ribotide

Supplementary material

10495_2013_850_MOESM1_ESM.doc (951 kb)
Supplementary material 1 (DOC 952 kb)


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Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  • Diana M. González-Gironès
    • 1
  • Cristina Moncunill-Massaguer
    • 1
  • Daniel Iglesias-Serret
    • 1
  • Ana M. Cosialls
    • 1
  • Alba Pérez-Perarnau
    • 1
  • Claudia M. Palmeri
    • 1
  • Camila Rubio-Patiño
    • 1
  • Andreas Villunger
    • 2
  • Gabriel Pons
    • 1
  • Joan Gil
    • 1
  1. 1.Departament de Ciències Fisiològiques IIInstitut d’Investigació Biomèdica de Bellvitge (IDIBELL)–Universitat de BarcelonaBarcelonaSpain
  2. 2.Division of Developmental ImmunologyBiocenter, Innsbruck Medical UniversityInnsbruckAustria

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