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Ahmad Al Moujahed, Fotini Nicolaou, Thanos Papakostas, Joan Miller, Evangelos Gragoudas, Demetrios Vavvas; Uveal Melanoma Cells Are Inhibited by AICAR Partially Through Activation of AMP-Dependent Kinase. Invest. Ophthalmol. Vis. Sci. 2013;54(15):4525.
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© ARVO (1962-2015); The Authors (2016-present)
5-Aminoimidazole-4-carboxamide-1-β-4-ribofuranoside (AICAR), an analog of AMP is widely used as an activator of AMP-kinase (AMPK), a protein that regulates the cell energy homeostasis and response to metabolic stress. The purpose of this study is to evaluate the effects of AICAR, AMPK activator, on the growth of uveal melanoma cell lines (OCM3 and MEL92.1)
Two different cell lines (OCM3, MEL92.1) were treated with AICAR (1-4 mM) for 3-5 days. Cell growth was assessed by MTT assay. Cell cycle analysis was assessed with propidium iodide staining and flow cytometry. Expression of cell cycle regulators (Cyclins, p21, p27, PCNA , CDK2 and CDK4), Acetyl-CoA Carboxylase, S6, 4E-binding protein 1 and the autophagy marker LC3 was assessed by RT-PCR and Western blots.
Cell treatment with AICAR inhibited cell growth, induced S-phase cell cycle arrest and led to activation of AMPK. These effects were abolished by treatment with dypiridamole, an inhibitor of AICAR entrance into cells. Treatment with adenosine kinase inhibitor 5-iodotubericidin to inhibit the conversion of AICAR to ZMP (the direct activator of AMPK) reversed a significant part of the growth inhibiting effects of AICAR indicating that some of AICAR’s anti-proliferative effect are mediated through AMPK activation. In addition, AICAR treatment was associated with upregulation of the autophagy marker LC3, downregulation of 4EBP1 phosphorylation via mammalian target of rapamycin (mTOR) independent mechanism, and down-regulation of cyclins A and D.
Our results indicate that AICAR-induced activation of AMPK inhibits uveal melanoma cell growth. This is one of few descriptions of low toxicity drug that may be effective in treating uveal melanoma patients.
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