5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside inhibits cancer cell proliferation in vitro and in vivo via AMP-activated protein kinase
5-Aminoimidazole-4-carboxamide-1-β-D-ribofuranoside inhibits cancer cell proliferation in vitro and in vivo via AMP-activated protein kinase
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DOI：
10.1074/jbc.m507443200
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发表时间：
2005-11-25
影响因子：
4.8
通讯作者：
Singh, I
中科院分区：
文献类型：
--
作者：
Rattan, R;Giri, S;Singh, I
5-氨基咪唑-4-甲酰胺-1-β-4-呋喃核糖苷（AICAR）作为AMP激酶激活剂被广泛使用，其调节能量稳态和对代谢应激的反应。在此，我们研究了AMPK激活剂AICAR对各种癌细胞增殖的影响，并观察到AICAR处理显著抑制了所有受检细胞系的增殖，这是由于S期阻滞伴随着p21、p27和p53蛋白表达增加以及PI 3 K-Akt通路的抑制。癌细胞体外生长的抑制在体内反映为p21、p27和p53表达的增加和Akt磷酸化的减弱。AICAR的抗增殖作用是通过激活AMP活化蛋白激酶（AMPK）介导的，因为碘结核菌素和显性负性AMPK表达载体逆转AICAR介导的生长停滞。此外，组成性活性AMPK通过诱导p21、p27和p53蛋白的表达和抑制Akt磷酸化而将细胞阻滞在S期，表明AMPK参与其中。当转染LKB显性负性表达载体时，AICAR对LKB和LKB敲除小鼠胚胎成纤维细胞的增殖抑制程度相似，并将细胞阻滞在S期。总之，这些结果表明AICAR可以用作抑制癌症的治疗药物，并且AMPK可以是独立于功能性肿瘤抑制基因LKB的用于治疗各种癌症的潜在靶点。
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.