Nuclear localization of human spermine oxidase isoforms - possible implications in drug response and disease etiology.

Abstract

The recent discovery of the direct oxidation of spermine via spermine oxidase (SMO) as a mechanism through which specific antitumor polyamine analogues exert their cytotoxic effects has fueled interest in the study of the polyamine catabolic pathway. A major byproduct of spermine oxidation is H2O2, a source of toxic reactive oxygen species. Recent targeted small interfering RNA studies have confirmed that SMO-produced reactive oxygen species are directly responsible for oxidative stress capable of inducing apoptosis and potentially mutagenic DNA damage. In the present study, we describe a second catalytically active splice variant protein of the human spermine oxidase gene, designated SMO5, which exhibits substrate specificities and affinities comparable to those of the originally identified human spermine oxidase-1, SMO/PAOh1, and, as such, is an additional source of H2O2. Importantly, overexpression of either of these SMO isoforms in NCI-H157 human non-small cell lung carcinoma cells resulted in significant localization of SMO protein in the nucleus, as determined by confocal microscopy. Furthermore, cell lines overexpressing either SMO/PAOh1 or SMO5 demonstrated increased spermine oxidation in the nucleus, with accompanying alterations in individual nuclear polyamine concentrations. This increased oxidation of spermine in the nucleus therefore increases the production of highly reactive H2O2 in close proximity to DNA, as well as decreases nuclear spermine levels, thus altering the protective roles of spermine in free radical scavenging and DNA shielding, and resulting in an overall increased potential for oxidative DNA damage in these cells. The results of these studies therefore have considerable significance both with respect to targeting polyamine oxidation as an antineoplastic strategy, and in regard to the potential role of spermine oxidase in inflammation-induced carcinogenesis.

• Authors: Tracy Murray-Stewart, Yanlin Wang, Andrew Goodwin, Amy Hacker, Alan Meeker, Robert A Casero Jr
• Journal: The FEBS journal (FEBS J) Vol. 275 Issue 11 Pg. 2795-806 (Jun 2008) ISSN: 1742-464X [Print] England
• PMID: 18422650 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Polyamines
• Protein Isoforms
• Reactive Oxygen Species
• Hydrogen Peroxide
• Oxidoreductases Acting on CH-NH Group Donors
• polyamine oxidase

Topics

• Alternative Splicing
• Cell Line, Tumor
• Cell Nucleus (metabolism)
• Chemistry, Pharmaceutical (methods)
• DNA Damage
• Drug Design
• Humans
• Hydrogen Peroxide (chemistry)
• Models, Chemical
• Models, Genetic
• Oxidoreductases Acting on CH-NH Group Donors (chemistry)
• Polyamines (chemistry)
• Protein Isoforms
• Reactive Oxygen Species
• Substrate Specificity