AICAR induces apoptosis independently of AMPK and p53 through upregulation of the BH3-only proteins BIM and NOXA in chronic lymphocytic leukemia cells

July 28, 2010

BlankBlood First Edition Paper, prepublished online July 27, 2010; DOI

10.1182/blood-2010-05-283960.

AICAR induces apoptosis independently of AMPK and p53 through upregulation of

the BH3-only proteins BIM and NOXA in chronic lymphocytic leukemia cells

F. Santidrián1, M. González-Gironès1, Iglesias-Serret1,

Llorenç Coll-Mulet1, Ana M. Cosialls1, Mercè de Frias1, Clara Campàs1, Eva

González-Barca2, Esther Alonso3, Verena Labi4, Benoit Viollet5, Adalberto

Benito6, Pons1, s Villunger4 and Joan Gil1,*

1 Departament de Ciencies Fisiologiques II, Institut d'Investigacio Biomedica de

Bellvitge (IDIBELL)-Universitat de Barcelona, L'Hospitalet del Llobregat, Spain;

2 Departament d'Hematologia Clinica, IDIBELL-Institut Catala d'Oncologia,

L'Hospitalet del Llobregat, Spain; 3 Servei d'Hematologia, IDIBELL-Hospital de

Bellvitge, L'Hospitalet del Llobregat, Spain; 4 Division of Developmental

Immunology, Biocenter, Innsbruck Medical University, Innsbruck, Austria; 5

Institut Cochin, Universite Paris Descartes, CNRS (UMR 8104), Paris, France; 6

Servicio de Nefrologia, Hospital Universitario Marques de Valdecilla-IFIMAV,

Santander, Spain

* Corresponding author; email: jgil@...

Abstract

AICAR (5-aminoimidazole-4-carboxamide riboside or acadesine) induces apoptosis

in chronic lymphocytic leukemia (CLL) cells. A clinical study of AICAR is

currently being performed in patients with this disease. Here, we have analyzed

the mechanisms involved in AICAR-induced apoptosis in CLL cells in which it

activates its only well known molecular target, adenosine

monophosphate-activated protein kinase (AMPK). However, AMPK activation with

phenformin or A-769662 failed to induce apoptosis in CLL cells and AICAR also

potently induced apoptosis in B lymphocytes from AMPK(alpha)1-/- mice,

demonstrating an AMPK-independent mechanism of cell death. Importantly, AICAR

induced apoptosis irrespective of the tumor suppressor TP53 or ataxia

telangiectasia mutated (ATM) status via induction of the mitochondrial pathway.

Apoptosis was preceded by an increase in mRNA and protein levels of proapoptotic

BCL-2 family proteins of the BH3-only subgroup including BIM, NOXA, and PUMA in

CLL cells. Strikingly, B lymphocytes from NOXA-/- or BIM-/- mice were partially

protected from the cytotoxic effects of AICAR. Consistently, B cells from

NOXA-/-/BIM-/- mice resisted induction of apoptosis by AICAR as potently as B

lymphocytes overexpressing transgenic BCL-2. These findings support the notion

that AICAR is an interesting alternative therapeutic option for CLL patients

with impaired p53 function and resistance to conventional chemotherapy.

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