Abstract
Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is a lipid and protein phosphatase that coordinates various cellular processes. Its activity is regulated by the reversible oxidation of an active-site cysteine residue by H2O2 and thioredoxin. However, the potential role of lipid peroxides in the redox regulation of PTEN remains obscure. To evaluate this, 15-hydroperoxy-eicosatetraenoic acid (15s-HpETE), a lipid peroxide, was employed to investigate its effect on PTEN using molecular and cellular-based assays. Exposure to 15s-HpETE resulted in the oxidation of recombinant PTEN. Reversible oxidation of PTEN was also observed in mouse embryonic fibroblast (MEF) cells treated with a 15s-HpETE and Lipofectamine mixture. The oxidative dimerization of thioredoxin was found simultaneously. In addition, the absence of peroxiredoxin III aggravated 15s-HpETE-induced PTEN oxidation in MEF cells. Our study provides novel insight into the mechanism linking lipid peroxidation to the etiology of tumorigenesis.
Highlights
Lipoxygenases (LOX) are a heterogeneous family of enzymes that catalyze the insertion of molecular oxygen into polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA) and linoleic acid (LA), into the corresponding hydroperoxyl derivates, which can be potent inflammatory and prooxidant mediators [1, 2]. 15-Lipoxygenase (15-LOX), a member of the LOX family, is widely expressed in different organisms [3,4,5,6,7,8]. 15-LOX metabolizes AA to form 15(s)hydroperoxyeicosatetraenoic acid (15s-HpETE), the oxidative precursor of 15-hydroxyeicosatetraenoic acid (15s-HETE). 15s-HpETE, 15s-HETE, and many of their analogous metabolites have important physiological functions
Our results demonstrated a previously unrecognized ability of endogenous lipid peroxides in the redox regulation of tumor suppressor PTEN
Exposure of recombinant PTEN to 15s-HpETE resulted in increases of faster migrating bands in nonreducing SDS-PAGE, and such effects were completely reversed by treatment with DTT. 15sHpETE-mediated cellular PTEN oxidation was identical to oxidation by H2O2, suggesting that an identical intramolecular disulfide bond was formed after 15s-HpETE treatment. 15s-HpETE was unable to induce cellular PTEN oxidation in C2C12, HeLa, or HT22 cells
Summary
Lipoxygenases (LOX) are a heterogeneous family of enzymes that catalyze the insertion of molecular oxygen into polyunsaturated fatty acids (PUFAs), such as arachidonic acid (AA) and linoleic acid (LA), into the corresponding hydroperoxyl derivates, which can be potent inflammatory and prooxidant mediators [1, 2]. 15-Lipoxygenase (15-LOX), a member of the LOX family, is widely expressed in different organisms [3,4,5,6,7,8]. 15-LOX metabolizes AA to form 15(s)hydroperoxyeicosatetraenoic acid (15s-HpETE), the oxidative precursor of 15-hydroxyeicosatetraenoic acid (15s-HETE). 15s-HpETE, 15s-HETE, and many of their analogous metabolites have important physiological functions. 15-LOX metabolizes AA to form 15(s)hydroperoxyeicosatetraenoic acid (15s-HpETE), the oxidative precursor of 15-hydroxyeicosatetraenoic acid (15s-HETE). Emerging evidence has suggested that 15sHpETE-induced membrane lipid peroxidation and free radical generation [9] may exert proinflammatory properties and contribute to endothelial cell injury [13]. Both 15sHpETE and 15s-HETE were shown to inhibit the growth of cultured human chronic myelogenous leukemia K562 cells by a mechanism associated with reactive oxygen species (ROS) [11, 14, 15]. Both 15sHpETE and 15s-HETE were shown to inhibit the growth of cultured human chronic myelogenous leukemia K562 cells by a mechanism associated with reactive oxygen species (ROS) [11, 14, 15]. 15s-HpETE and 15s-HETE formed during
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
