Conditional expression of 15-lipoxygenase-1 inhibits the selenoenzyme thioredoxin reductase. Modulation of selenoproteins by lipoxygenase enzymes

Margaret K. Yu, Philip J. Moos, Pamela Cassidy, Mark Wade, F. A. Fitzpatrick

Research output: Contribution to journalArticle

29 Citations (Scopus)

Abstract

The selenoenzyme thioredoxin reductase regulates redox-sensitive proteins involved in inflammation and carcinogenesis, including ribonucleotide reductase, p55, NFκB, and others. Little is known about endogenous cellular factors that modulate thioredoxin reductase activity. Here we report that several metabolites of 15-lipoxygenase-1 inhibit purified thioredoxin reductase in vitro. 15(S)-Hydroperoxy-5,8,11-cis-15-trans-eico-satetraenoic acid, a metastable hydroperoxide generated by 15-lipoxygenase-1, and 4-hydroxy-2-nonenal, its non-enzymatic rearrangement product inhibit thioredoxin reductase with IC50 = 13 ± 1.5 μM and 1 ± 0.2 μM, respectively. Endogenously generated metabolites of 15-lipoxygenase-1 also inhibit thioredoxin reductase in HEK-293 cells that harbor a 15-LOX-1 gene under the control of an inducible promoter complex. Conditional, highly selective induction of 15-lipoxygenase-1 caused an inhibition of ribonucleotide reductase activity, cell cycle arrest in G1, impairment of anchorage-independent growth, and accumulation of the pro-apoptotic protein BAX. All of these responses are consistent with inhibition of thioredoxin reductase via 15-lipoxygenase-1 overexpression. In contrast, metabolites of 5-lipoxygenase were poor inhibitors of isolated thioredoxin reductase, and the overexpression of 5-lipoxygenase did not inhibit thioredoxin reductase or cause a G1 cell cycle arrest. The influences of 15-lipoxygenase-1 on inflammation, cell growth, and survival may be attributable, in part, to inhibition of thioredoxin reductase and several redox-sensitive processes subordinate to thioredoxin reductase.

Original languageEnglish (US)
Pages (from-to)28028-28035
Number of pages8
JournalJournal of Biological Chemistry
Volume279
Issue number27
DOIs
StatePublished - Jul 2 2004
Externally publishedYes

Fingerprint

Arachidonate 15-Lipoxygenase
Selenoproteins
Thioredoxin-Disulfide Reductase
Lipoxygenase
Modulation
Enzymes
Metabolites
Ribonucleotide Reductases
Arachidonate 5-Lipoxygenase
Oxidation-Reduction
Cells
Inflammation
G1 Phase Cell Cycle Checkpoints
Activity Cycles
Apoptosis Regulatory Proteins
HEK293 Cells
Cell growth
Growth
Ports and harbors
Cell Cycle Checkpoints

ASJC Scopus subject areas

  • Biochemistry

Cite this

Conditional expression of 15-lipoxygenase-1 inhibits the selenoenzyme thioredoxin reductase. Modulation of selenoproteins by lipoxygenase enzymes. / Yu, Margaret K.; Moos, Philip J.; Cassidy, Pamela; Wade, Mark; Fitzpatrick, F. A.

In: Journal of Biological Chemistry, Vol. 279, No. 27, 02.07.2004, p. 28028-28035.

Research output: Contribution to journalArticle

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