Amino Acids

, Volume 42, Issue 2, pp 529–538

Knockdown of ornithine decarboxylase antizyme 1 causes loss of uptake regulation leading to increased N1, N11-bis(ethyl)norspermine (BENSpm) accumulation and toxicity in NCI H157 lung cancer cells

  • Alison V. Fraser
  • Andrew C. Goodwin
  • Amy Hacker-Prietz
  • Elizabeth Sugar
  • Patrick M. Woster
  • Robert A. CaseroJr.
Original Article

DOI: 10.1007/s00726-011-1030-z

Cite this article as:
Fraser, A.V., Goodwin, A.C., Hacker-Prietz, A. et al. Amino Acids (2012) 42: 529. doi:10.1007/s00726-011-1030-z
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Abstract

Ornithine decarboxylase antizyme 1 (AZ1) is a major regulatory protein responsible for the regulation and degradation of ornithine decarboxylase (ODC). To better understand the role of AZ1 in polyamine metabolism and in modulating the response to anticancer polyamine analogues, a small interfering RNA strategy was used to create a series of stable clones in human H157 non-small cell lung cancer cells that expressed less than 5–10% of basal AZ1 levels. Antizyme 1 knockdown clones accumulated greater amounts of the polyamine analogue N1,N11-bis(ethyl)norspermine (BENSpm) and were more sensitive to analogue treatment. The possibility of a loss of polyamine uptake regulation in the knockdown clones was confirmed by polyamine uptake analysis. These results are consistent with the hypothesis that AZ1 knockdown leads to dysregulation of polyamine uptake, resulting in increased analogue accumulation and toxicity. Importantly, there appears to be little difference between AZ1 knockdown cells and cells with normal levels of AZ1 with respect to ODC regulation, suggesting that another regulatory protein, potentially AZ2, compensates for the loss of AZ1. The results of these studies are important for the understanding of both the regulation of polyamine homeostasis and in understanding the factors that regulate tumor cell sensitivity to the anti-tumor polyamine analogues.

Keywords

AntizymeOrnithine decarboxylasePolyaminesSpermineBENSpm

Abbreviations

AZ1

Ornithine decarboxylase antizyme 1

ODC

Ornithine decarboxylase

NSCLC

Non-small cell lung cancer

BENSpm

N1,N11-bis(ethyl)norspermine

AZin

Ornithine decarboxylase antizyme inhibitor

siRNA

Small interfering RNA

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Alison V. Fraser
    • 1
  • Andrew C. Goodwin
    • 1
  • Amy Hacker-Prietz
    • 1
  • Elizabeth Sugar
    • 1
  • Patrick M. Woster
    • 2
  • Robert A. CaseroJr.
    • 1
  1. 1.Department of Oncology, The Sidney Kimmel Comprehensive Cancer CenterJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Department of Pharmaceutical and Biomedical SciencesMedical University of South CarolinaCharlestonUSA