5-Aminoimidazole-4-carboxamide-1-beta-4-ribofuranoside (
AICAR) is widely used as an
AMP-kinase activator, which regulates energy homeostasis and response to metabolic stress. Here, we investigated the effect of
AICAR, an AMPK activator, on proliferation of various
cancer cells and observed that proliferation of all the examined cell lines was significantly inhibited by
AICAR treatment due to arrest in S-phase accompanied with increased expression of p21, p27, and p53
proteins and inhibition of PI3K-Akt pathway. Inhibition in in vitro growth of
cancer cells was mirrored in vivo with increased expression of p21, p27, and p53 and attenuation of Akt phosphorylation. Anti-proliferative effect of
AICAR is mediated through activated
AMP-activated protein kinase (AMPK) as iodotubericidin and dominant-negative AMPK expression vector reversed the
AICAR-mediated growth arrest. Moreover, constitutive active AMPK arrested the cells in S-phase by inducing the expression of p21, p27, and p53
proteins and inhibiting Akt phosphorylation, suggesting the involvement of AMPK.
AICAR inhibited proliferation in both LKB and LKB knock-out mouse embryo fibroblasts to similar extent and arrested cells at S-phase when transfected with dominant negative expression vector of LKB. Altogether, these results indicate that
AICAR can be utilized as a therapeutic drug to inhibit
cancer, and AMPK can be a potential target for treatment of various
cancers independent of the functional tumor suppressor gene, LKB.