15-Deoxy-Δ12,14-prostaglandin J2 induces Cox-2 expression in human osteosarcoma cells through MAPK and EGFR activation involving reactive oxygen species

Kitz, Kerstin; Windischhofer, Werner; Leis, Hans Jörg; Huber, Eveline; Kollroser, Manfred; Malle, Ernst

doi:10.1016/j.freeradbiomed.2010.12.039

Cited by 31 publications

(43 citation statements)

References 66 publications

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“…e l s e v i e r . c o m / l o c a t e / i j c a r d PGJ 2 with ROS production in different cellular systems at lower (95-160 nM) [17] as well as higher concentrations (1-20 μM) [5,18,19]. We agree with Tsikas et al [1] on their view that direct therapeutic targeting of 15d-PGJ 2 would be a difficult task.…”

Section: Contents Lists Available At Sciencedirectsupporting

confidence: 88%

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Response to letter by Tsikas et al.

Koyani

Windischhofer

Rossmann

et al. 2014

International Journal of Cardiology

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Section: Contents Lists Available At Sciencedirectsupporting

confidence: 88%

“…We agree that concentrations of 15d-PGJ 2 (a degradation product of prostaglandin D 2 [PGD 2 ]) used in most in vitro studies [3][4][5] including ours (Figs. 1-6 [2]) are higher than occurring in vivo.…”

Section: Dear Editorsupporting

confidence: 86%

Response to letter by Tsikas et al.

Koyani

Windischhofer

Rossmann

et al. 2014

International Journal of Cardiology

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“…A detailed Materials and methods section on cell culture [27], isolation of primary murine cardiomyocytes [28], incubation protocols, Western blot analysis [22,29], RNA isolation and real time RT-PCR (qPCR) [30], TNFα RNA interference and silencing [22], reactive oxygen species (ROS) measurements [31], cell viability assay [31], TNFα ELISA experiments and statistics is available in the online Supplement.…”

Section: Methodsmentioning

confidence: 99%

“…However, recent findings confirm that 15d-PGJ 2 exerts a variety of cellular responses via PPARγ-independent mechanisms, e.g. activation of mitogen-activated protein kinases (MAPKs) [12,13], modulation of Akt and nuclear factor-κB (NF-κB) [14,15], induction of oxidative stress [16], expression of cytokines [17], promotion of apoptosis [18,19], up-regulation of antioxidant response genes [20,21] and modulation of COX-2 [22].…”

Section: Introductionmentioning

confidence: 99%

15-deoxy-Δ12,14-PGJ2 promotes inflammation and apoptosis in cardiomyocytes via the DP2/MAPK/TNFα axis

Koyani

Windischhofer

Rossmann

et al. 2014

International Journal of Cardiology

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BackgroundProstaglandins (PGs), lipid autacoids derived from arachidonic acid, play a pivotal role during inflammation. PGD2 synthase is abundantly expressed in heart tissue and PGD2 has recently been found to induce cardiomyocyte apoptosis. PGD2 is an unstable prostanoid metabolite; therefore the objective of the present study was to elucidate whether its final dehydration product, 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2, present at high levels in ischemic myocardium) might cause cardiomyocyte damage.Methods and resultsUsing specific (ant)agonists we show that 15d-PGJ2 induced formation of intracellular reactive oxygen species (ROS) and phosphorylation of p38 and p42/44 MAPKs via the PGD2 receptor DP2 (but not DP1 or PPARγ) in the murine atrial cardiomyocyte HL-1 cell line. Activation of the DP2-ROS-MAPK axis by 15d-PGJ2 enhanced transcription and translation of TNFα and induced apoptosis in HL-1 cardiomyocytes. Silencing of TNFα significantly attenuated the extrinsic (caspase-8) and intrinsic apoptotic pathways (bax and caspase-9), caspase-3 activation and downstream PARP cleavage and γH2AX activation. The apoptotic machinery was unaffected by intracellular calcium, transcription factor NF-κB and its downstream target p53. Of note, 9,10-dihydro-15d-PGJ2 (lacking the electrophilic carbon atom in the cyclopentenone ring) did not activate cellular responses. Selected experiments performed in primary murine cardiomyocytes confirmed data obtained in HL-1 cells namely that the intrinsic and extrinsic apoptotic cascades are activated via DP2/MAPK/TNFα signaling.ConclusionsWe conclude that the reactive α,β-unsaturated carbonyl group of 15d-PGJ2 is responsible for the pronounced upregulation of TNFα promoting cardiomyocyte apoptosis. We propose that inhibition of DP2 receptors could provide a possibility to modulate 15d-PGJ2-induced myocardial injury.

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“…Cyclooxygenase (COX) is the rate-limiting enzyme for the production of prostaglandins and thromboxanes from free arachidonic acid (Kitz et al , 2011). COX exists as two distinct isoforms, the constitutively expressed enzyme COX-1 and the inducible isoform COX-2 (Smith et al , 1996).…”

Section: Introductionmentioning

confidence: 99%

Ethanol enhances arsenic-induced cyclooxygenase-2 expression via both NFAT and NF-κB signalings in colorectal cancer cells

Wang

Hitron

Wise

et al. 2015

Toxicology and Applied Pharmacology

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Arsenic is a known carcinogen to humans, and chronic exposure to environmental arsenic is a worldwide health concern. As a dietary factor, ethanol carries a well-established risk for malignancies, but the effects of co-exposure to arsenic and ethanol on tumor development are not well understood. In the present study, we hypothesized that ethanol would enhance the function of an environmental carcinogen such as arsenic through increase in COX-2 expression. Our in vitro results show that ethanol enhanced arsenic-induced COX-2 expression. We also show that the increased COX-2 expression associates with intracellular ROS generation, up-regulated AKT signaling, with activation of both NFAT and NF-κB pathways. We demonstrate that antioxidant enzymes have an inhibitory effect on arsenic/ethanol-induced COX-2 expression, indicating that the responsive signaling pathways from co-exposure to arsenic and ethanol relate to ROS generation. In vivo results also show that co-exposure to arsenic and ethanol increased COX-2 expression in mice. We conclude that ethanol enhances arsenic-induced COX-2 expression in colorectal cancer cells via both the NFAT and NF-κB pathways. These results imply that, as a common dietary factor, ethanol ingestion may be a compounding risk factor for arsenic-induced carcinogenesis/cancer development.

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15-Deoxy-Δ12,14-prostaglandin J2 induces Cox-2 expression in human osteosarcoma cells through MAPK and EGFR activation involving reactive oxygen species

Cited by 31 publications

References 66 publications

Response to letter by Tsikas et al.

Response to letter by Tsikas et al.

15-deoxy-Δ12,14-PGJ2 promotes inflammation and apoptosis in cardiomyocytes via the DP2/MAPK/TNFα axis

Ethanol enhances arsenic-induced cyclooxygenase-2 expression via both NFAT and NF-κB signalings in colorectal cancer cells

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