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

S. K. Radhakrishnan, M. Halasi, U. G. Bhat, R. T. Kurmasheva, Peter J Houghton, A. L. Gartel

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)694-699
Number of pages6
JournalOncogene
Volume27
Issue number5
DOIs
StatePublished - Jan 24 2008
Externally publishedYes

Fingerprint

AIDS-Related Complex
Neuroblastoma
Apoptosis
Cell Line
Nucleosides
Down-Regulation
Dichlororibofuranosylbenzimidazole
Oncogenes
Caspase 3
Neoplasms
Cell Death

Keywords

  • Akt
  • ARC
  • Mcl-1
  • N-myc
  • Neuroblastoma
  • Survivin

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Radhakrishnan, S. K., Halasi, M., Bhat, U. G., Kurmasheva, R. T., Houghton, P. J., & Gartel, A. L. (2008). Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells. Oncogene, 27(5), 694-699. https://doi.org/10.1038/sj.onc.1210692

Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells. / Radhakrishnan, S. K.; Halasi, M.; Bhat, U. G.; Kurmasheva, R. T.; Houghton, Peter J; Gartel, A. L.

In: Oncogene, Vol. 27, No. 5, 24.01.2008, p. 694-699.

Research output: Contribution to journalArticle

Radhakrishnan, SK, Halasi, M, Bhat, UG, Kurmasheva, RT, Houghton, PJ & Gartel, AL 2008, 'Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells', Oncogene, vol. 27, no. 5, pp. 694-699. https://doi.org/10.1038/sj.onc.1210692
Radhakrishnan SK, Halasi M, Bhat UG, Kurmasheva RT, Houghton PJ, Gartel AL. Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells. Oncogene. 2008 Jan 24;27(5):694-699. https://doi.org/10.1038/sj.onc.1210692
Radhakrishnan, S. K. ; Halasi, M. ; Bhat, U. G. ; Kurmasheva, R. T. ; Houghton, Peter J ; Gartel, A. L. / Proapoptotic compound ARC targets Akt and N-myc in neuroblastoma cells. In: Oncogene. 2008 ; Vol. 27, No. 5. pp. 694-699.
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