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

Authors

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

DOI: 10.1007/s10495-013-0850-6

Cite this article as:
González-Gironès, D.M., Moncunill-Massaguer, C., Iglesias-Serret, D. et al. Apoptosis (2013) 18: 1008. doi:10.1007/s10495-013-0850-6

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

Abbreviations

ACC

Acetyl-CoA carboxylase

AICAR

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

AMPK

AMP-activated protein kinase

CLL

Chronic lymphocytic leukemia

DKO

Double knockout

MEFs

Mouse embryonic fibroblasts

MOMP

Mitochondrial outer membrane permeabilization

PI

Propidium iodide

RT-MLPA

Reverse transcriptase multiplex ligation-dependent probe amplification

RT-qPCR

Real time quantitative PCR

SEM

Standard error of the mean

WT

Wild type

ZMP

AICA ribotide

Supplementary material

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

Copyright information

© Springer Science+Business Media New York 2013