Uveal Melanoma Cell Growth Is Inhibited by Aminoimidazole Carboxamide Ribonucleotide (AICAR) Partially Through Activation of AMP-Dependent Kinase

被引:11
作者
Al-Moujahed, Ahmad [1 ]
Nicolaou, Fotini [2 ]
Brodowska, Katarzyna [1 ]
Papakostas, Thanos D. [1 ]
Marmalidou, Anna [1 ]
Ksander, Bruce R. [3 ]
Miller, Joan W. [1 ]
Gragoudas, Evangelos [1 ]
Vavvas, Demetrios G. [1 ]
机构
[1] Harvard Univ, Massachusetts Eye & Ear Infirm, Sch Med, Retina Serv,Angiogenesis Lab,Dept Ophthalmol, Boston, MA 02114 USA
[2] Massachusetts Gen Hosp, Pediat Surg Labs, Boston, MA 02114 USA
[3] Harvard Univ, Sch Med, Massachusetts Eye & Ear, Schepens Eye Res Inst,Dept Ophthalmol, Boston, MA 02114 USA
关键词
AMPK; AICAR; melanoma; mTOR; RIBOSIDE INDUCES APOPTOSIS; PROTON-BEAM IRRADIATION; FATTY-ACID OXIDATION; PROTEIN-KINASE; PROGNOSTIC-FACTORS; OCULAR MELANOMA; MAPK PATHWAY; KEY SENSOR; PHOSPHORYLATION; EXPRESSION;
D O I
10.1167/iovs.13-12856
中图分类号
R77 [眼科学];
学科分类号
100212 ;
摘要
PURPOSE. To evaluate the effects and mechanism of aminoimidazole carboxamide ribonucleotide (AICAR), an AMP-dependent kinase (AMPK) activator, on the growth of uveal melanoma cell lines. METHODS. Four different cell lines were treated with AICAR (1-4 mM). Cell growth was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay. Cell cycle analysis was conducted by flow cytometry; additionally, expression of cell-cycle control proteins, cell growth transcription factors, and downstream effectors of AMPK were determined by RT-PCR and Western blot. RESULTS. Aminoimidazole carboxamide ribonucleotide inhibited cell growth, induced S-phase arrest, and led to AMPK activation. Aminoimidazole carboxamide ribonucleotide treatment was associated with inhibition of eukaryotic translation initiation factor 4E-BP1 phosphorylation, a marker of mammalian target of rapamycin (mTOR) pathway activity. Aminoimidazole carboxamide ribonucleotide treatment was also associated with downregulation of cyclins A and D, but had minimal effects on the phosphorylation of ribosomal protein S6 or levels of the macroautophagy marker LC3B. The effects of AICAR were abolished by treatment with dipyridamole, an adenosine transporter inhibitor that blocks the entry of AICAR into cells. Treatment with adenosine kinase inhibitor 5-iodotubericidin, which inhibits the conversion of AICAR to its 5'-phosphorylated ribotide 5-aminoimidazole-4-carboxamide-1-D-ribofuranosyl-5'-monophosphate (ZMP; the direct activator of AMPK), reversed most of the growth-inhibitory effects, indicating that some of AICAR's antiproliferative effects are mediated at least partially through AMPK activation. CONCLUSIONS. Aminoimidazole carboxamide ribonucleotide inhibited uveal melanoma cell proliferation partially through activation of the AMPK pathway and downregulation of cyclins A1 and D1.
引用
收藏
页码:4175 / 4185
页数:11
相关论文
共 77 条
[1]   Role of AMPK-mTOR-Ulk1/2 in the Regulation of Autophagy: Cross Talk, Shortcuts, and Feedbacks [J].
Alers, Sebastian ;
Loeffler, Antje S. ;
Wesselborg, Sebastian ;
Stork, Bjoern .
MOLECULAR AND CELLULAR BIOLOGY, 2012, 32 (01) :2-11
[2]  
[Anonymous], 2008, DRUGS R&D, V9, P169
[3]   Effectiveness of Treatments for Metastatic Uveal Melanoma [J].
Augsburger, James J. ;
Correa, Zelia M. ;
Shaikh, Adeel H. .
AMERICAN JOURNAL OF OPHTHALMOLOGY, 2009, 148 (01) :119-127
[4]   Activation of adenosine monophosphate activated protein kinase inhibits growth of multiple myeloma cells [J].
Baumann, Philipp ;
Mandl-Weber, Sonja ;
Emmerich, Bertold ;
Straka, Christian ;
Schmidmaier, Ralf .
EXPERIMENTAL CELL RESEARCH, 2007, 313 (16) :3592-3603
[5]  
Bedikian Agop Y., 2006, International Ophthalmology Clinics, V46, P151, DOI 10.1097/01.iio.0000195852.08453.de
[6]   Expression of MAGE genes in ocular melanoma during progression from primary to metastatic disease [J].
Chen, PW ;
Murray, TG ;
Uno, T ;
Salgaller, ML ;
Reddy, R ;
Ksander, BR .
CLINICAL & EXPERIMENTAL METASTASIS, 1997, 15 (05) :509-518
[7]  
CORTON JM, 1995, EUR J BIOCHEM, V229, P558, DOI 10.1111/j.1432-1033.1995.tb20498.x
[8]   AMP-activated protein kinase is highly expressed in neurons in the developing rat brain and promotes neuronal survival following glucose deprivation [J].
Culmsee, C ;
Monnig, J ;
Kemp, BE ;
Mattson, MP .
JOURNAL OF MOLECULAR NEUROSCIENCE, 2001, 17 (01) :45-58
[9]   Does ocular treatment of uveal melanoma influence survival? [J].
Damato, B. .
BRITISH JOURNAL OF CANCER, 2010, 103 (03) :285-290
[10]   TISSUE DISTRIBUTION OF THE AMP-ACTIVATED PROTEIN-KINASE, AND LACK OF ACTIVATION BY CYCLIC-AMP-DEPENDENT PROTEIN-KINASE, STUDIED USING A SPECIFIC AND SENSITIVE PEPTIDE ASSAY [J].
DAVIES, SP ;
CARLING, D ;
HARDIE, DG .
EUROPEAN JOURNAL OF BIOCHEMISTRY, 1989, 186 (1-2) :123-128