Original Paper

Apoptosis

, Volume 18, Issue 8, pp 1008-1016

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

  • Diana M. González-GironèsAffiliated withDepartament de Ciències Fisiològiques II, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL)–Universitat de Barcelona
  • , Cristina Moncunill-MassaguerAffiliated withDepartament de Ciències Fisiològiques II, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL)–Universitat de Barcelona
  • , Daniel Iglesias-SerretAffiliated withDepartament de Ciències Fisiològiques II, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL)–Universitat de Barcelona
  • , Ana M. CosiallsAffiliated withDepartament de Ciències Fisiològiques II, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL)–Universitat de Barcelona
  • , Alba Pérez-PerarnauAffiliated withDepartament de Ciències Fisiològiques II, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL)–Universitat de Barcelona
  • , Claudia M. PalmeriAffiliated withDepartament de Ciències Fisiològiques II, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL)–Universitat de Barcelona
  • , Camila Rubio-PatiñoAffiliated withDepartament de Ciències Fisiològiques II, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL)–Universitat de Barcelona
  • , Andreas VillungerAffiliated withDivision of Developmental Immunology, Biocenter, Innsbruck Medical University
  • , Gabriel PonsAffiliated withDepartament de Ciències Fisiològiques II, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL)–Universitat de Barcelona
    • , Joan GilAffiliated withDepartament de Ciències Fisiològiques II, Institut d’Investigació Biomèdica de Bellvitge (IDIBELL)–Universitat de Barcelona Email author 

Rent the article at a discount

Rent now

* Final gross prices may vary according to local VAT.

Get Access

Abstract

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.

Keywords

AICAR Ampk Apoptosis Bim Noxa MEFs