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

Tracy Murray Stewart, Yanlin Wang, Andrew Goodwin, Amy Hacker, Alan Keith Meeker, Robert A Casero

Research output: Contribution to journalArticle

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 H 2O2, 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 H 2O2. 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.

Original languageEnglish (US)
Pages (from-to)2795-2806
Number of pages12
JournalFEBS Journal
Volume275
Issue number11
DOIs
StatePublished - Jun 2008

Fingerprint

Protein Isoforms
Spermine
Polyamines
Pharmaceutical Preparations
Oxidation
DNA
Cells
DNA Damage
Reactive Oxygen Species
polyamine oxidase
Oxidative stress
Confocal microscopy
Poisons
Scavenging
Substrate Specificity
Confocal Microscopy
Non-Small Cell Lung Carcinoma
Antineoplastic Agents
Shielding
Small Interfering RNA

Keywords

  • Carcinogenesis
  • HO
  • Oxidation
  • Polyamine
  • SMO

ASJC Scopus subject areas

  • Biochemistry

Cite this

Nuclear localization of human spermine oxidase isoforms - Possible implications in drug response and disease etiology. / Murray Stewart, Tracy; Wang, Yanlin; Goodwin, Andrew; Hacker, Amy; Meeker, Alan Keith; Casero, Robert A.

In: FEBS Journal, Vol. 275, No. 11, 06.2008, p. 2795-2806.

Research output: Contribution to journalArticle

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