Expression of MRP1 and GSTP1-1 modulate the acute cellular response to treatment with the chemopreventive isothiocyanate, sulforaphane

Sibhatu, Mebrahtu B.; Smitherman, Pamela K.; Townsend, Alan J.; Morrow, Charles S.

doi:10.1093/carcin/bgn013

Cited by 31 publications

(32 citation statements)

References 54 publications

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“…GSTP1-1 catalyzes the conjugation of various electrophilic compounds with the tripeptide glutathione (GSH), the adducts formed being substrates for cellular export by the multidrug transporter systems (Sibhatu et al, 2008). GSTP1-1 has also been found to promote the glutathionylation of cellular proteins (Townsend et al, 2009), a process that can be considered a protective mechanism against irreversible oxidative damage and requires the catalytic activity of the enzyme.…”

Section: Introductionmentioning

confidence: 99%

Cyclopentenone Prostaglandins with Dienone Structure Promote Cross-Linking of the Chemoresistance-Inducing Enzyme Glutathione Transferase P1-1

Sánchez‐Gómez¹,

Díez-Dacal²,

Pajares³

et al. 2010

Mol Pharmacol

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Glutathione transferase P1-1 (GSTP1-1) plays crucial roles in cancer chemoprevention and chemoresistance and is a key target for anticancer drug development. Oxidative stress or inhibitor-induced GSTP1-1 oligomerization leads to the activation of stress cascades and apoptosis in various tumor cells. Therefore, bivalent glutathione transferase (GST) inhibitors with the potential to interact with GST dimers are been sought as pharmacological and/or therapeutic agents. Here we have characterized GSTP1-1 oligomerization in response to various endogenous and exogenous agents. Ethacrynic acid, a classic GSTP1-1 inhibitor, 4-hydroxy-nonenal, hydrogen peroxide, and diamide all induced reversible GSTP1-1 oligomerization in Jurkat leukemia cells through the formation of disulphide bonds involving Cys47 and/or Cys101, as suggested by reducing and nonreducing SDS-polyacrylamide gel electrophoresis analysis of cysteine to serine mutants. Remarkably, the electrophilic prostanoid 15-deoxy-⌬ 12,14 -prostaglandin J 2 (15d-PGJ 2 ) induced irreversible GSTP1-1 oligomerization, specifically involving Cys101, a residue present in the human but not in the murine enzyme. 15d-PGJ 2 -induced GSTP1-1 cross-linking required the prostaglandin (PG) dienone structure and was associated with sustained c-Jun NH 2 -terminal kinase activation and induction of apoptosis. It is noteworthy that 15d-PGJ 2 elicited GSTP1-1 cross-linking in vitro, a process that could be mimicked by other dienone cyclopentenone PG, such as ⌬ 12 -PGJ 2 , and by the bifunctional thiol reagent dibromobimane, suggesting that cyclopentenone PG may be directly involved in oligomer formation. Remarkably, ⌬ 12 -PGJ 2 -induced oligomeric species were clearly observed by electron microscopy showing dimensions compatible with GSTP1-1 tetramers. These results provide the first direct visualization of GSTP1-1 oligomeric species. Moreover, they offer novel strategies for the modulation of GSTP1-1 cellular functions, which could be exploited to overcome its role in cancer chemoresistance.

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Section: Introductionmentioning

confidence: 99%

Cyclopentenone Prostaglandins with Dienone Structure Promote Cross-Linking of the Chemoresistance-Inducing Enzyme Glutathione Transferase P1-1

Sánchez‐Gómez¹,

Díez-Dacal²,

Pajares³

et al. 2010

Mol Pharmacol

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“…Cells were harvested after 24 hr continuous exposure to vehicle or inducing agent. Luciferase assays were accomplished using the Dual Luciferase Assay System (Promega, Madison, WI) and values were corrected for variations in transfection efficiencies and non-specific induction as described previously 26. All incubations, including transfections and inductions, were done in Dulbecco's modified Eagle medium supplemented with 10% fetal bovine serum.…”

Section: Methodsmentioning

confidence: 99%

Activation of Peroxisome Proliferator-Activated Receptor γ (PPARγ) by Nitroalkene Fatty Acids: Importance of Nitration Position and Degree of Unsaturation

et al. 2009

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Nitroalkene fatty acids are potent endogenous ligand activators of PPARγ-dependent transcription. Previous studies with the naturally occurring regioisomers of nitrolinoleic acid revealed that the isomers are not equivalent with respect to PPARγ activation. To gain further insight into the structureactivity relationships between nitroalkenes and PPARγ, we examined additional naturally occurring nitroalkenes derived from oleic acid, 9-nitrooleic acid (E-9-NO 2 -18:1 [1]) and 10-nitrooleic acid (E-10-NO 2 -18:1 [2]), and several synthetic nitrated enoic fatty acids of variable carbon chain length, double bonds, and nitration site. At submicromolar concentrations, E-12-NO 2 derivatives were considerably more potent than isomers nitrated at carbons 5, 6, 9, 10 or 13; and, chain length (16 versus 18) or number of double bonds (one versus two) was of little consequence for PPARγ activation. Interestingly, at higher concentrations (> 2 μM) the nitrated enoic fatty acids (E-9-NO 2 -18:1 [1], E-9-NO 2 -16:1 [3], E-10-NO 2 -18:1 [2], and E-12-NO 2 -18:1 [7]) deviated significantly from the saturable pattern of PPARγ activation observed for nitrated 1,4-dienoic fatty acids

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“…Cells were harvested 24 hours after the start of exposure to vehicle or inducing agent. Luciferase assays were accomplished using the Dual Luciferase Assay System (Promega, Madison, WI) and values were corrected for variations in transfection efficiencies and non-specific induction as described previously (23). …”

Section: Methodsmentioning

confidence: 99%

Noncatalytic Interactions between Glutathione S-Transferases and Nitroalkene Fatty Acids Modulate Nitroalkene-Mediated Activation of Peroxisomal Proliferator-Activated Receptor γ

et al. 2009

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The naturally occurring nitroalkenes, nitrolinoleic (NO2-LA) and nitrooleic (NO2-OA) acids, are among the most potent endogenous ligand activators of PPARγ-dependent transcription. In order to understand mechanisms that regulate cellular response to these nitroalkenes, we previously demonstrated that glutathione conjugation of NO2-LA and MRP1-mediated efflux of the conjugates were associated with significant attenuation of PPARγ activation by this nitroalkene (Biochemistry 45: 7889-7896, 2006). Here we show that NO2-OA activation of PPARγ is similarly affected by non-enzymatic conjugation and MRP1-mediated efflux. Moreover, the roles of glutathione S-transferases (GSTs) in the glutathione conjugation and bioactivities of NO2-LA and NO2-OA were investigated. While none of the GST isozymes tested (GSTA1-1, A4-4, M1a-1a, and P1a-1a) enhanced the rate of glutathione conjugation, expression of GSTA1-1, M1a-1a or P1a-1a in MCF7 cells significantly reduced the magnitude of PPARγ-dependent reporter gene transcription in response to NO2-LA and NO2-OA treatment—with GSTP1a-1a expression mediating the most potent inhibition of PPARγ. Although these GSTs failed to catalyze nitroalkene conjugation with glutathione, the nitroalkenes were found to associate avidly with all four GST isozymes as indicated by their ability to inhibit GST activity with Ki's in the nanomolar range. Treatment of purified GSTP1a-1a with excess NO2-LA and NO2-OA resulted in the formation of covalent adducts between GSTP1a monomers and nitroalkenes; although, separate experiments indicated that such covalent bond formation was not necessary for avid GST-nitroalkene interactions. These results suggest that GSTs can inhibit the activation of transcription by nitroalkenes via non-catalytic sequestration of these ligands, and their glutathione conjugates, away from their nuclear target, PPARγ.

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Expression of MRP1 and GSTP1-1 modulate the acute cellular response to treatment with the chemopreventive isothiocyanate, sulforaphane

Cited by 31 publications

References 54 publications

Cyclopentenone Prostaglandins with Dienone Structure Promote Cross-Linking of the Chemoresistance-Inducing Enzyme Glutathione Transferase P1-1

Cyclopentenone Prostaglandins with Dienone Structure Promote Cross-Linking of the Chemoresistance-Inducing Enzyme Glutathione Transferase P1-1

Activation of Peroxisome Proliferator-Activated Receptor γ (PPARγ) by Nitroalkene Fatty Acids: Importance of Nitration Position and Degree of Unsaturation

Noncatalytic Interactions between Glutathione S-Transferases and Nitroalkene Fatty Acids Modulate Nitroalkene-Mediated Activation of Peroxisomal Proliferator-Activated Receptor γ

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