Retinoblastoma cells are inhibited by aminoimidazole carboxamide ribonucleotide (AICAR) partially through activation of AMP-dependent kinase

Sofia Theodoropoulou, Paraskevi E. Kolovou, Yuki Morizane, Maki Kayama, Fotini Nicolaou, Joan W. Miller, Evangelos Gragoudas, Bruce R. Ksander, Demetrios G. Vavvas

Research output: Contribution to journalArticlepeer-review

26 Citations (Scopus)

Abstract

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 responses of the cell to energy change. We studied the effects of AICAR on the growth of retinoblastoma cell lines (Y79, WERI, and RB143). AICAR inhibited Rb cell growth, induced apoptosis and S-phase cell cycle arrest, and led to activation of AMPK. These effects were abolished by treatment with dypiridamole, an inhibitor that blocks entrance of AICAR into cells. Treatment with the adenosine kinase inhibitor 5-iodotubericidin to inhibit the conversion of AICAR to ZMP (the direct activator of AMPK) reversed most of the growth-inhibiting effects of AICAR, indicating that some of the antiproliferative effects of AICAR are mediated through AMPK activation. In addition, AICAR treatment was associated with inhibition of the mammalian target of rapamycin pathway, decreased phosphorylation of ribosomal protein-S6 and 4E-BP1, down-regulation of cyclins A and E, and decreased expression of p21. Our results indicate that AICAR-induced activation of AMPK inhibits retinoblastoma cell growth. This is one of the first descriptions of a nonchemotherapeutic drug with low toxicity that may be effective in treating Rb patients.

Original languageEnglish
Pages (from-to)2620-2630
Number of pages11
JournalFASEB Journal
Volume24
Issue number8
DOIs
Publication statusPublished - Aug 2010
Externally publishedYes

Keywords

  • Cancer
  • Energy
  • Eye
  • Intraocular tumors
  • Metabolism

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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