This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Koomoa, D.-L. T. Articles by Bachmann, A. S. Search for Related Content PubMed PubMed Citation Articles by Koomoa, D.-L. T. Articles by Bachmann, A. S.

Ornithine Decarboxylase Inhibition by -Difluoromethylornithine Activates Opposing Signaling Pathways via Phosphorylation of Both Akt/Protein Kinase B and p27^Kip1 in Neuroblastoma

¹ Cancer Research Center of Hawaii, ² Department of Cell and Molecular Biology, John A. Burns School of Medicine, and ³ Department of Molecular Biosciences and Bioengineering, University of Hawaii at Manoa, Honolulu, Hawaii

Requests for reprints: André S. Bachmann, Cancer Research Center of Hawaii, Natural Products and Cancer Biology Program, University of Hawaii at Manoa, 1236 Lauhala Street, Honolulu, HI 96813. Phone: 808-586-2962; Fax: 808-586-2970; E-mail: abachmann{at}crch.hawaii.edu.

Key Words: Akt/PKB • p27^Kip1 • DFMO • neuroblastoma • ornithine decarboxylase • polyamines

Ornithine decarboxylase (ODC) is a key enzyme in mammalian polyamine biosynthesis that is up-regulated in various types of cancer. We previously showed that treating human neuroblastoma (NB) cells with the ODC inhibitor -difluoromethylornithine (DFMO) depleted polyamine pools and induced G₁ cell cycle arrest without causing apoptosis. However, the precise mechanism by which DFMO provokes these changes in NB cells remained unknown. Therefore, we further examined the effects of DFMO, alone and in combination with phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 or Akt/protein kinase B (PKB) inhibitor IV, on the regulation of cell survival and cell cycle–associated pathways in LAN-1 NB cells. In the present study, we found that the inhibition of ODC by DFMO promotes cell survival by inducing the phosphorylation of Akt/PKB at residue Ser⁴⁷³ and glycogen synthase kinase-3β at Ser⁹. Intriguingly, DFMO also induced the phosphorylation of p27^Kip1 at residues Ser¹⁰ (nuclear export) and Thr¹⁹⁸ (protein stabilization) but not Thr¹⁸⁷ (proteasomal degradation). The combined results from this study provide evidence for a direct cross-talk between ODC-dependent metabolic processes and well-established cell signaling pathways that are activated during NB tumorigenesis. The data suggest that inhibition of ODC by DFMO induces two opposing pathways in NB: one promoting cell survival by activating Akt/PKB via the PI3K/Akt pathway and one inducing p27^Kip1/retinoblastoma-coupled G₁ cell cycle arrest via a mechanism that regulates the phosphorylation and stabilization of p27^Kip1. This study presents new information that may explain the moderate efficacy of DFMO monotherapy in clinical trials and reveals potential new targets for DFMO-based combination therapies for NB treatment. [Cancer Res 2008;68(23):9825–31]

This article has been cited by other articles:

				N. F. Evageliou and M. D. Hogarty Disrupting Polyamine Homeostasis as a Therapeutic Strategy for Neuroblastoma Clin. Cancer Res., October 1, 2009; 15(19): 5956 - 5961. [Abstract] [Full Text] [PDF]

				D.-L. T. Koomoa, T. Borsics, D. J. Feith, C. C. Coleman, C. J. Wallick, I. Gamper, A. E. Pegg, and A. S. Bachmann Inhibition of S-adenosylmethionine decarboxylase by inhibitor SAM486A connects polyamine metabolism with p53-Mdm2-Akt/protein kinase B regulation and apoptosis in neuroblastoma Mol. Cancer Ther., July 1, 2009; 8(7): 2067 - 2075. [Abstract] [Full Text] [PDF]