OXER1, a G protein-coupled oxoeicosatetraenoid receptor, mediates the survival-promoting effects of arachidonate 5-lipoxygenase in prostate cancer cells

Sarveswaran, Sivalokanathan; Ghosh, J. J.

doi:10.1016/j.canlet.2013.04.027

Cited by 34 publications

(39 citation statements)

References 49 publications

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“…The proliferative effects of 5-oxo-ETE on prostate cancer cells appear to be mediated by activation of PLC-β, resulting in the release of diacyl glycerol and activation of PKC-ε [204,205]. Consistent with these findings, the OXE receptor is expressed in a variety of tumor cell lines from different sources [164], including prostate tumors [230].…”

Section: Biological Actions Of Hetes and Oxoetesmentioning

confidence: 94%

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Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid

Powell

Rokach

2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

245

200

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Arachidonic acid can be oxygenated by a variety of different enzymes, including lipoxygenases, cyclooxygenases, and cytochrome P450s, and can be converted to a complex mixture of oxygenated products as a result of lipid peroxidation. The initial products in these reactions are hydroperoxyeicosatetraenoic acids (HpETEs) and hydroxyeicosatetraenoic acids (HETEs). Oxoeicosatetraenoic acids (oxo-ETEs) can be formed by the actions of various dehydrogenases on HETEs or by dehydration of HpETEs. Although a large number of different HETEs and oxo-ETEs have been identified, this review will focus principally on 5-oxo-ETE, 5S-HETE, 12S-HETE, and 15S-HETE. Other related arachidonic acid metabolites will also be discussed in less detail. 5-Oxo-ETE is synthesized by oxidation of the 5-lipoxygenase product 5S-HETE by the selective enzyme, 5-hydroxyeicosanoid dehydrogenase. It actions are mediated by the selective OXE receptor, which is highly expressed on eosinophils, suggesting that it may be important in eosinophilic diseases such as asthma. 5-Oxo-ETE also appears to stimulate tumor cell proliferation and may also be involved in cancer. Highly selective and potent OXE receptor antagonists have recently become available and could help to clarify its pathophysiological role. The 12-lipoxygenase product 12S-HETE acts by the GPR31 receptor and promotes tumor cell proliferation and metastasis and could therefore be a promising target in cancer therapy. It may also be involved as a proinflammatory mediator in diabetes. In contrast, 15S-HETE may have a protective effect in cancer. In addition to GPCRs, higher concentration of HETEs and oxo-ETEs can activate peroxisome proliferator-activated receptors (PPARs) and could potentially regulate a variety of processes by this mechanism.

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Section: Biological Actions Of Hetes and Oxoetesmentioning

confidence: 94%

“…There is also evidence for the participation of various PKC isoforms in the response to 5-oxo-ETE, including PLC-δ, PKC-ζ [126], and PKC-ε [204]. 5-Oxo-ETE also stimulates the phosphorylation of MAP kinases, including ERK-1, ERK-2 [103,126,162,163], and p38 [126,208].…”

Section: Biological Actions Of Hetes and Oxoetesmentioning

confidence: 99%

Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid

Powell

Rokach

2015

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

245

200

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“…Blocking its expression with siRNA reduced the viability of PC3 cells, lending further support for a role for 5-oxo-ETE as an endogenous regulator of prostate tumor cell growth [111]. The proliferative effect of 5-oxo-ETE on these cells appears to be mediated through PLC-β, release of diacyl glycerol, and activation of PKC-ε [112,113]. …”

Section: Effects Of 5-oxo-ete On Different Cell Typesmentioning

confidence: 99%

The eosinophil chemoattractant 5-oxo-ETE and the OXE receptor

Powell

Rokach

2013

Progress in Lipid Research

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5-Oxo-ETE (5-oxo-6,8,11,14-eicosatetraenoic acid) is formed from the 5-lipoxygenase product 5-HETE (5S-hydroxy-6,8,11,14-eicosatetraenoic acid) by 5-hydroxyeicosanoid dehydrogenase (5-HEDH). The cofactor NADP+ is a limiting factor in the synthesis of 5-oxo-ETE because of its low concentrations in unperturbed cells. Activation of the respiratory burst in phagocytic cells, oxidative stress, and cell death all dramatically elevate both intracellular NADP+ levels and 5-oxo-ETE synthesis. 5-HEDH is widely expressed in inflammatory, structural, and tumor cells. Cells devoid of 5-lipoxygenase can synthesize 5-oxo-ETE by transcellular biosynthesis using inflammatory cell-derived 5-HETE. 5-Oxo-ETE is a chemoattractant for neutrophils, monocytes, and basophils and promotes the proliferation of tumor cells. However, its primary target appears to be the eosinophil, for which it is a highly potent chemoattractant. The actions of 5-oxo-ETE are mediated by the highly selective OXE receptor, which signals by activating various second messenger pathways through the release of the βγ-dimer from Gi/o proteins to which it is coupled. Because of its potent effects on eosinophils, 5-oxo-ETE may be an important mediator in asthma, and, because of its proliferative effects, may also contribute to tumor progression. Selective OXE receptor antagonists, which are currently under development, could be useful therapeutic agents in asthma and other allergic diseases.

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“…However, lingering problems with solubility and bioavailability of several available 5-Lox inhibitors have limited their use for prostate cancer therapy. Based on published reports about the 5-Lox inhibitory effect of WDL, we expected that WDL will inhibit c-Myc and induce apoptosis in prostate cancer cells as we recently observed with other 5-Lox inhibitors (31 32…”

Section: Discussionmentioning

confidence: 91%

“…Moreover, the transcriptional activity of c-Myc as well as the invasive and soft-agar colony forming abilities of prostate cancer cells are also down-regulated upon treatment with WDL. We reported earlier that WDL inhibits PKC-epsilon while inducing apoptosis in prostate cancer cells (11), and that PKC-epsilon has emerged as a newly characterized signaling intermediate in the 5-oxoETE/OXER1-driven prostate cancer cell-survival pathway (31,32). PKC-epsilon has been found to phosphorylate and activate Stat3 (33,34), and inhibition of Stat3 down-regulates expression of c-Myc gene in prostate cancer cells (25), suggesting that the inhibitory effect of WDL on c-Myc function in prostate cancer cells may be mediated via inhibition of PKC-epsilon and Stat3-mediated transcription of the c-Myc gene.…”

Section: Introductionmentioning

confidence: 99%

Wedelolactone, an Anti-inflammatory Botanical, Interrupts c-Myc Oncogenic Signaling and Synergizes with Enzalutamide to Induce Apoptosis in Prostate Cancer Cells

Sarveswaran

Ghosh

Parikh

et al. 2016

Molecular Cancer Therapeutics

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The c-Myc gene encodes an oncoprotein transcription factor which is frequently up-regulated in almost all cancer types, and is the subject of intense investigation for management of cancer because of its pleiotropic effects controlling a spectrum of cellular functions. However, due of its non-enzymatic nature, development of suitable strategies to block its protein-protein or protein-DNA interaction is challenging. Thus, c-Myc has been recognized as an elusive molecular target for cancer control and various approaches are in development to inhibit c-Myc-transcriptional activity. We observed that wedelolactone (WDL), an anti-inflammatory botanical compound, severely down-regulates the expression of c-Myc mRNA in prostate cancer cells. Moreover, WDL dramatically decreases the protein level, nuclear localization, DNA-binding, and transcriptional activities of c-Myc. c-Myc is a transforming oncogene widely expressed in prostate cancer cells and is critical for maintaining their transformed phenotype. Interestingly, WDL was found to strongly affect the viability of Myc-activated prostate cancer cells, and completely blocks their invasion as well as soft-agar colony-formation in vitro. WDL was also found to down-regulate c-Myc in vivo in nude mice xenografts. Moreover, WDL synergizes with enzalutamide to decrease the viability of androgen-sensitive prostate cancer cells via induction of apoptosis. These findings reveal a novel anticancer mechanism of the natural compound, WDL, and suggest that the oncogenic function of c-Myc in prostate cancer cells can be effectively down-regulated by WDL for the development of a new therapeutic strategy against Myc-driven prostate cancer.

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OXER1, a G protein-coupled oxoeicosatetraenoid receptor, mediates the survival-promoting effects of arachidonate 5-lipoxygenase in prostate cancer cells

Cited by 34 publications

References 49 publications

Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid

Biosynthesis, biological effects, and receptors of hydroxyeicosatetraenoic acids (HETEs) and oxoeicosatetraenoic acids (oxo-ETEs) derived from arachidonic acid

The eosinophil chemoattractant 5-oxo-ETE and the OXE receptor

Wedelolactone, an Anti-inflammatory Botanical, Interrupts c-Myc Oncogenic Signaling and Synergizes with Enzalutamide to Induce Apoptosis in Prostate Cancer Cells

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