Specificity of arachidonic acid-induced inhibition of growth and activation of c-jun kinases and p38 mitogen-activated protein kinase in hematopoietic cells

Rizzo, Maria Teresa; Pudlo, Nancy; Farrell, Lindsey; Leaver, Anne

doi:10.1054/plef.2001.0330

Cited by 13 publications

(8 citation statements)

References 31 publications

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“…Among the 90 predictions with P < 0.05, the predominantly observed pattern indicated proteins involved in the processing and recognition of arachidonic acid (AA). In fact, AA exhibits specific antiproliferative effects by currently unknown mechanisms of action 33 . From a chemoinformatics perspective, these predictions were intriguing because neither AA nor its derivatives were part of our reference database, but instead originated from largely disjointed reference sets.…”

Section: Resultsmentioning

confidence: 99%

Revealing the macromolecular targets of complex natural products

Reker¹,

Perna²,

Rodrigues³

et al. 2014

Nature Chem

120

102

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Natural products have long been a source of useful biological activity for the development of new drugs. Their macromolecular targets are, however, largely unknown, which hampers rational drug design and optimization. Here we present the development and experimental validation of a computational method for the discovery of such targets. The technique does not require three-dimensional target models and may be applied to structurally complex natural products. The algorithm dissects the natural products into fragments and infers potential pharmacological targets by comparing the fragments to synthetic reference drugs with known targets. We demonstrate that this approach results in confident predictions. In a prospective validation, we show that fragments of the potent antitumour agent archazolid A, a macrolide from the myxobacterium Archangium gephyra, contain relevant information regarding its polypharmacology. Biochemical and biophysical evaluation confirmed the predictions. The results obtained corroborate the practical applicability of the computational approach to natural product 'de-orphaning'.

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Section: Resultsmentioning

confidence: 99%

Revealing the macromolecular targets of complex natural products

Reker¹,

Perna²,

Rodrigues³

et al. 2014

Nature Chem

120

102

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“…Western blot analyses for the detection of COX-2 were done as we described previously (33). To detect mPGES-1 and cPGES-1 protein expression, cells were lysed using the experimental conditions employed for the detection of COX-2 (33).…”

Section: Measurement Of Prostaglandin Levels From Cell Supernatantsmentioning

confidence: 99%

“…Equal amounts of total proteins were resolved by gel electrophoresis, transferred to nitrocellulose membranes, and subjected to immunoblotting using the following primary antibodies: rabbit polyclonal anti-COX-2 (1:1,000); rabbit polyclonal anti-mPGES-1 (1:1,000); rabbit polyclonal anti-cPGES (1:1,000); rabbit polyclonal anti-EP1, anti-EP2, anti-EP3, and anti-EP4 receptors (1:1,000); chicken polyclonal anti-PKA I (1:1,000); and rabbit polyclonal anti-PKA II (1:2,500). Following incubation with the appropriate horseradish peroxidase -linked secondary antibodies, proteins were visualized by the enhanced chemiluminescence detection system as we described previously (33).…”

Section: Measurement Of Prostaglandin Levels From Cell Supernatantsmentioning

confidence: 99%

Microsomal prostaglandin E synthase-1 regulates human glioma cell growth via prostaglandin E2–dependent activation of type II protein kinase A

Payner¹,

Leaver

Knapp

et al. 2006

Molecular Cancer Therapeutics

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Dysregulation of enzymes involved in prostaglandin biosynthesis plays a critical role in influencing the biological behavior and clinical outcome of several tumors. In human gliomas, overexpression of cyclooxygenase-2 has been linked to increased aggressiveness and poor prognosis. In contrast, the role of prostaglandin E synthase in influencing the biological behavior of human gliomas has not been established. We report that constitutive expression of the microsomal prostaglandin E synthase-1 (mPGES-1) is associated with increased prostaglandin E 2 (PGE 2 ) production and stimulation of growth in the human astroglioma cell line U87-MG compared with human primary astrocytes. Consistently, pharmacologic and genetic inhibition of mPGES-1 activity and expression blocked the release of PGE 2 from U87-MG cells and decreased their proliferation. Conversely, exogenous PGE 2 partially overcame the antiproliferative effects of mPGES-1 inhibition and stimulated U87-MG cell proliferation in the absence of mPGES-1 inhibitors. The EP2/EP4 subtype PGE 2 receptors, which are linked to stimulation of adenylate cyclase, were expressed in U87-MG cells to a greater extent than in human astrocytes. PGE 2 increased cyclic AMP levels and stimulated protein kinase A (PKA) activity in U87-MG cells. Treatment with a selective type II PKA inhibitor decreased PGE 2 -induced U87-MG cell proliferation, whereas a selective type I PKA inhibitor had no effect. Taken together, these results are consistent with the hypothesis that mPGES-1 plays a critical role in promoting astroglioma cell growth via PGE 2 -dependent activation of type II PKA.

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“…PUFA/ HUFA release may occur at the plasma membrane, or at intracellular membranes, such as endoplasmic reticulum and mitochondrial membranes. AA and other PUFA may exert direct effects on stress signalling factors and genes (Rizzo et al ., 1999; 2002). AA regulates gene expression directly via p38 MAPK, ERK and JNK, increasing transcription of AP‐1‐containing genes.…”

Section: Pufa Release Under Pathological Conditionsmentioning

confidence: 99%

Therapeutic implications of disorders of cell death signalling: membranes, micro‐environment, and eicosanoid and docosanoid metabolism

Davidson

Rotondo

Rizzo

et al. 2012

British J Pharmacology

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Disruptions of cell death signalling occur in pathological processes, such as cancer and degenerative disease. Increased knowledge of cell death signalling has opened new areas of therapeutic research, and identifying key mediators of cell death has become increasingly important. Early triggering events in cell death may provide potential therapeutic targets, whereas agents affecting later signals may be more palliative in nature. A group of primary mediators are derivatives of the highly unsaturated fatty acids (HUFAs), particularly oxygenated metabolites such as prostaglandins. HUFAs, esterified in cell membranes, act as critical signalling molecules in many pathological processes. Currently, agents affecting HUFA metabolism are widely prescribed in diseases involving disordered cell death signalling. However, partly due to rapid metabolism, their role in cell death signalling pathways is poorly characterized. Recently, HUFA-derived mediators, the resolvins/protectins and endocannabinoids, have added opportunities to target selective signals and pathways. This review will focus on the control of cell death by HUFA, eicosanoid (C20 fatty acid metabolites) and docosanoid (C22 metabolites), HUFA-derived lipid mediators, signalling elements in the micro-environment and their potential therapeutic applications. Further therapeutic approaches will involve cell and molecular biology, the multiple hit theory of disease progression and analysis of system plasticity. Advances in the cell biology of eicosanoid and docosanoid metabolism, together with structure/function analysis of HUFA-derived mediators, will be useful in developing therapeutic agents in pathologies characterized by alterations in cell death signalling. AbbreviationsDHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; NSAID, nonsteroidal anti-inflammatory drug; PG, prostaglandin; AA, arachidonic acid; HUFA, highly unsaturated fatty acids with 4 or more bonds, for example, arachidonic, eicosapentaenoic and docosahexaenoic acids (4, 5 and 6 double bonds respectively); PUFA, polyunsaturated fatty acids, with 2 or more unsaturated C-C bonds; HUFA, highly unsaturated C20 fatty acid, with 3 or more unsaturated C-C bonds Many therapeutic agents influence cell death signalling and highly unsaturated fatty acid (HUFA) metabolism (Figure 1). These agents may act at the level of metabolic events affecting apoptosis, enzyme systems and cofactors, agents affecting cell cycle progression and DNA repair, and oncogene expression. Intracellularly, agents affecting organelles and the mitochondrial intrinsic pathway, endoplasmic reticulumassociated stress pathways and lysosomal autophagy can have profound effects on cell death. There has also been development of agents affecting transcellular signalling via the extrinsic pathway, oxidative stress, growth factors and lipid mediators, ion and metabolite flux, adhesion and migration.

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Specificity of arachidonic acid-induced inhibition of growth and activation of c-jun kinases and p38 mitogen-activated protein kinase in hematopoietic cells

Cited by 13 publications

References 31 publications

Revealing the macromolecular targets of complex natural products

Revealing the macromolecular targets of complex natural products

Microsomal prostaglandin E synthase-1 regulates human glioma cell growth via prostaglandin E2–dependent activation of type II protein kinase A

Therapeutic implications of disorders of cell death signalling: membranes, micro‐environment, and eicosanoid and docosanoid metabolism

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