期刊
JOURNAL OF BIOLOGICAL CHEMISTRY
卷 278, 期 28, 页码 26046-26054出版社
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M303690200
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Prostaglandin (PG) D-2, a major cyclooxygenase product in a variety of tissues and cells, readily undergoes dehydration to yield the bioactive cyclopentenone-type PGs of the J(2) series, such as 15-deoxy-Delta(12,14)-PGJ(2) (15d-PGJ(2)). We have shown previously that 15d-PGJ(2) is a potent electrophile that causes intracellular oxidative stress and redox alteration in human neuroblastoma SH-SY5Y cells. In the present study, based on the observation that the electrophilic center of 15d-PGJ(2) was involved in the pro-oxidant effect, we investigated the role of thioredoxin 1 (Trx), an endogenous redox regulator, against 15d-PGJ(2)-induced oxidative cell injury. It was observed that the 15d-PGJ(2)-induced oxidative stress was significantly suppressed by the Trx overexpression. In addition, the treatment of SH-SY5Y cells with biotinylated 15d-PGJ(2) resulted in the formation of a 15d-PGJ(2)-Trx adduct, indicating that 15d-PGJ(2) directly modified the endogenous Trx in the cells. To further examine the mechanism of the 15d-PGJ(2) modification of Trx, human recombinant Trx treated with 15d-PGJ(2) was analyzed by mass spectrometry. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry analysis of the 15d-PGJ(2)-treated human recombinant Trx demonstrated the addition of one molecule of 15d-PGJ(2) per protein molecule. Moreover, the electrospray ionization-liquid chromatography/mass spectrometry/mass spectrometry analysis identified two cysteine residues, Cys-35 and Cys-69, as the targets of 15d-PGJ(2). These residues may represent the direct sensors of the electrophilic PGs that induce the intracellular redox alteration and neuronal cell death.
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