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Select cyclopentenone prostaglandins trigger glutathione efflux and the role of ABCG2 transport.

ABSTRACT: Electrophilic cyclopentenone prostaglandins (cyPGs), such as 15-deoxy-Delta(12,14)-prostaglandin J(2) (15dPGJ(2)), initiate redox-based cell signaling responses including increased intracellular glutathione (GSH) synthesis. We investigated whether cyPGs facilitated GSH efflux and if members of the ATP-binding cassette (ABC) protein family mediated the efflux. Four human cell lines were treated with 1-6 microM cyPGs for 48 h. Media and cells were harvested for GSH measurements using HPLC-EC. CyPG treatment increased extracellular GSH levels two- to threefold over controls in HN4 and C38 cells and five- to sixfold in SAEC and MDA 1586 cells and was dependent on increased GSH synthesis. Our studies show that prostaglandin D(2) and its metabolites, prostaglandin J(2) and 15dPGJ(2), specifically induce GSH efflux compared to other eicosanoids. These higher extracellular GSH levels were associated with protection from tert-butylhydroperoxide. Superarray analysis of ABC transporters suggested only ABCG2 expression had a positive relationship in the four cell types compared with extracellular GSH increases after cyPG treatment. The ABCG2 substrate Hoechst 33342 inhibited extracellular GSH increase after 15dPGJ(2) treatment. We report for the first time that ABCG2 may play a role in GSH efflux in response to cyPG treatment and may link inflammatory signaling with antioxidant adaptive responses.

SUBMITTER: Brechbuhl HM

PROVIDER: S-EPMC2730198 | biostudies-literature | 2009 Sep

REPOSITORIES: biostudies-literature

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Select cyclopentenone prostaglandins trigger glutathione efflux and the role of ABCG2 transport.

Brechbuhl Heather M HM Min Elysia E Kariya Chirag C Frederick Barbara B Raben David D Day Brian J BJ

Free radical biology & medicine 20090609 6

Electrophilic cyclopentenone prostaglandins (cyPGs), such as 15-deoxy-Delta(12,14)-prostaglandin J(2) (15dPGJ(2)), initiate redox-based cell signaling responses including increased intracellular glutathione (GSH) synthesis. We investigated whether cyPGs facilitated GSH efflux and if members of the ATP-binding cassette (ABC) protein family mediated the efflux. Four human cell lines were treated with 1-6 microM cyPGs for 48 h. Media and cells were harvested for GSH measurements using HPLC-EC. CyPG ...[more]

PMID: 19520157

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Project description:BACKGROUND: Despite the profound variation among marine consumers in tolerance for allelochemically-rich foods, few studies have examined the biochemical adaptations underlying diet choice. Here we examine the role of glutathione S-transferases (GSTs) in the detoxification of dietary allelochemicals in the digestive gland of the predatory gastropod Cyphoma gibbosum, a generalist consumer of gorgonian corals. Controlled laboratory feeding experiments were used to investigate the influence of gorgonian diet on Cyphoma GST activity and isoform expression. Gorgonian extracts and semi-purified fractions were also screened to identify inhibitors and possible substrates of Cyphoma GSTs. In addition, we investigated the inhibitory properties of prostaglandins (PGs) structurally similar to antipredatory PGs found in high concentrations in the Caribbean gorgonian Plexaura homomalla. PRINCIPAL FINDINGS: Cyphoma GST subunit composition was invariant and activity was constitutively high regardless of gorgonian diet. Bioassay-guided fractionation of gorgonian extracts revealed that moderately hydrophobic fractions from all eight gorgonian species examined contained putative GST substrates/inhibitors. LC-MS and NMR spectral analysis of the most inhibitory fraction from P. homomalla subsequently identified prostaglandin A(2) (PGA(2)) as the dominant component. A similar screening of commercially available prostaglandins in series A, E, and F revealed that those prostaglandins most abundant in gorgonian tissues (e.g., PGA(2)) were also the most potent inhibitors. In vivo estimates of PGA(2) concentration in digestive gland tissues calculated from snail grazing rates revealed that Cyphoma GSTs would be saturated with respect to PGA(2) and operating at or near physiological capacity. SIGNIFICANCE: The high, constitutive activity of Cyphoma GSTs is likely necessitated by the ubiquitous presence of GST substrates and/or inhibitors in this consumer's gorgonian diet. This generalist's GSTs may operate as 'all-purpose' detoxification enzymes, capable of conjugating or sequestering a broad range of lipophilic gorgonian compounds, thereby allowing this predator to exploit a range of chemically-defended prey, resulting in a competitive dietary advantage for this species.

Project description:Prostate stem cells (PSC) are characterized by their intrinsic resistance to androgen deprivation therapy (ADT), possibly due to the lack of androgen receptor (AR) expression. PSCs resistance to ADT and PSC expansion in castration resistant prostate cancer (CRPC) has sparked great interest in using differentiation therapy as an adjuvant to ADT. Understanding the mechanisms, by which PSCs maintain their undifferentiated phenotype, thus has important implications in differentiation therapy. In the prostate, the ATP binding cassette sub-family G member 2 (ABCG2) transporters, which enrich for AR-positive, ADT-resistant PSCs, play an important role in regulating the intracellular androgen levels by effluxing androgens. We hypothesized that the ABCG2-mediated androgen efflux is responsible for maintaining PSCs in an undifferentiated state. Using the HPr-1-AR (nontumorigenic) and CWR-R1 (tumorigenic) prostate cell lines, it was demonstrated that inhibiting the ABCG2-mediated androgen efflux, with Ko143 (ABCG2 inhibitor), increased the nuclear AR expression due to elevated intracellular androgen levels. Increased nuclear translocation of AR is followed by increased expression of AR regulated genes, a delayed cell growth response, and increased luminal differentiation. Furthermore, Ko143 reduced tumor growth rates in mice implanted with ABCG2-expressing CWR-R1 cells. In addition, Ko143-treated mice had more differentiated tumors as evidenced by an increased percentage of CK8+/AR+ luminal cells and decreased percentage of ABCG2-expressing cells. Thus, inhibiting ABCG2-mediated androgen efflux forces the PSCs to undergo an AR-modulated differentiation to an ADT-sensitive luminal phenotype.ImplicationsThis study identifies the mechanism by which the prostate stem cell marker, ABCG2, plays a role in prostate stem cell maintenance and provides a rationale for targeting ABCG2 for differentiation therapy in prostate cancer. Mol Cancer Res; 15(2); 128-40. ©2016 AACR.

Dataset Information

Select cyclopentenone prostaglandins trigger glutathione efflux and the role of ABCG2 transport.

Publications

Select cyclopentenone prostaglandins trigger glutathione efflux and the role of ABCG2 transport.

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