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Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells

Oncogene volume 27, pages 694–699 (2008)Cite this article

Abstract

We have previously described the identification of a nucleoside analog transcriptional inhibitor ARC (4-amino-6-hydrazino-7-β-D-ribofuranosyl-7H-pyrrolo[2,3-d]-pyrimidine-5-carboxamide) that was able to induce apoptosis in cancer cell lines of different origin. Here, we report the characterization of ARC on a panel of neuroblastoma cell lines. We found that these cell lines were more than 10-fold sensitive to ARC than to the well-known nucleoside analog DRB (5,6-dichloro-1-β-D-ribofuranosylbenzimidazole), and that ARC-induced apoptosis proceeds through mitochondrial injury. Also, we observed that ARC-mediated cell death was accompanied by caspase-3 cleavage and repression of antiapoptotic proteins such as Mcl-1 and survivin. Conversely, we found that overexpression of Mcl-1-protected neuroblastoma cell line NB-1691 from ARC-induced apoptosis. Furthermore, we found that while ARC inhibited the phosphorylation of Akt Ser-473 in multiple cancer cell lines, forced expression of myristoylated Akt promoted resistance to ARC-induced apoptosis in neuroblastoma cells. In addition, we observed that ARC was able to downregulate the protein levels of N-myc, a commonly amplified oncogene in neuroblastomas, and Akt protected N-myc from ARC-induced downregulation. These data suggest that ARC may antagonize different antiapoptotic pathways and induce apoptosis in neuroblastoma cells via multiple mechanisms. Overall, ARC could represent an attractive candidate for anticancer drug development against neuroblastomas.

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Acknowledgements

We thank Dr Douglas Cress for the Mcl-1 construct and Dr Nissim Hay for the mAkt construct, MCF7-mAkt cells and Rat1a-mAkt cells. This work was supported by the start-up funds from the UIC Department of Medicine (AL Gartel), award from the UIC Campus Research Board (AL Gartel), CA23099 (PJ Houghton) and CA96696 (PJ Houghton).

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Author notes

  1. S K Radhakrishnan

    Present address: 5Current address: Division of Biology, California Institute of Technology, Pasadena, CA 91125, USA.,

  2. S K Radhakrishnan and M Halasi: These two authors contributed equally to this work.

Authors and Affiliations

  1. Department of Medicine, University of Illinois at Chicago, Chicago, IL, USA

    S K Radhakrishnan, U G Bhat & A L Gartel

  2. Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, USA

    S K Radhakrishnan & A L Gartel

  3. Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA

    M Halasi

  4. Department of Molecular Pharmacology, St Jude Children's Research Hospital, Memphis, TN, USA

    R T Kurmasheva & P J Houghton

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  1. S K Radhakrishnan
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  2. M Halasi
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  3. U G Bhat
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  4. R T Kurmasheva
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  5. P J Houghton
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  6. A L Gartel
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Correspondence to A L Gartel.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Radhakrishnan, S., Halasi, M., Bhat, U. et al. Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells. Oncogene 27, 694–699 (2008). https://doi.org/10.1038/sj.onc.1210692

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