Enhancement of Transformed Foci and Induction of Prostaglandins in Balb/c 3T3 Cells by Palytoxin: In Vitro Model Reproduces Carcinogenic Responses in Animal Models Regarding the Inhibitory Effect of Indomethacin and Reversal of Indomethacin's Effect by Exogenous Prostaglandins

Miura, Daisuke; Kobayashi, Masaru; Kakiuchi, Satoko; Kasahara, Yoshinori; Kondô, Shirô

doi:10.1093/toxsci/kfi342

Cited by 11 publications

(11 citation statements)

References 31 publications

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“…Third, palytoxin can stimulate the production and release of prostaglandins in Balb/c 3T3 cells, which can then interact with cells to stimulate ERK1/2 activation (Fig. 3C) (Miura et al, 2006). Further research is needed to determine how the cellular context affects the mechanisms by which palytoxin modulates different MAP kinases, and how this affects the biological response of the cell to palytoxin exposure.…”

Section: Discussionmentioning

confidence: 99%

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Modulation of protein kinase signaling cascades by palytoxin

Wattenberg¹

2011

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Although known for its acutely toxic action, palytoxin has also been identified as a type of carcinogenic agent called a tumor promoter. In general tumor promoters do not damage DNA, but instead contribute to carcinogenesis by disrupting the regulation of cellular signaling. The identification of palytoxin as a tumor promoter, together with the recognition that the Na + ,K + -ATPase is its receptor, led to research on how palytoxin triggers the modulation of signal transduction pathways. This review focuses on mitogen activated protein (MAP) kinases as mediators of palytoxin-stimulated signaling. MAP kinases are a family of serine/threonine kinases that relay a variety of signals to the cellular machinery that regulates cell fate and function. The studies discussed in this review investigated how palytoxin stimulates MAP kinase activity and, in turn, how MAP kinases mediate the response of cells to palytoxin.

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Section: Discussionmentioning

confidence: 99%

“…A study of the role of prostaglandins in the tumor promoting action of palytoxin in an in vitro Balb/c 3T3 cell transformation model indicates that palytoxin can also activate ERK1/2 through an autocrine mechanism (Miura et al, 2006). Balb/c 3T3 cells were initiated with 3-methylcholanthrene.…”

Section: Palytoxin Modulates Erk1/2 Activity In Cells That Expressmentioning

confidence: 99%

Modulation of protein kinase signaling cascades by palytoxin

Wattenberg¹

2011

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“…Alternatively, palytoxin may stimulate the release of agents from cells that stimulate the growth of neighboring cells or perhaps induce an inflammatory response that contributes to tumor promotion. For example, palytoxin stimulates arachidonic acid metabolism and the release of prostaglandins in other systems (Levine et al, 1986; Lazzaro et al, 1987; Miura et al, 2006). Our observation that palytoxin stimulates ERK5 activation in two different cell types suggests that the role of ERK5 should be examined in various types of systems in which palytoxinstimulates responses that are likely to be involved in carcinogenesis.…”

Section: Discussionmentioning

confidence: 99%

Extracellular signal regulated kinase 5 mediates signals triggered by the novel tumor promoter palytoxin

Charlson

Zeliadt

Wattenberg

2009

Toxicology and Applied Pharmacology

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Palytoxin is classified as a non-12-O-tetradecanoylphorbol-13-acetate (TPA)-type skin tumor because it does not bind to or activate protein kinase C. Palytoxin is thus a novel tool for investigating alternative signaling pathways that may affect carcinogenesis. We previously showed that palytoxin activates three major members of the mitogen activated protein kinase (MAPK) family, extracellular signal regulated kinase 1 and 2 (ERK1/2), c-Jun N-terminal kinase (JNK), and p38. Here we report that palytoxin also activates another MAPK family member, called ERK5, in HeLa cells and in keratinocytes derived from initiated mouse skin (308 cells). By contrast, TPA does not activate ERK5 in these cell lines. The major cell surface receptor for palytoxin is the Na+,K+-ATPase. Accordingly, ouabain blocked the ability of palytoxin to activate ERK5. Ouabain alone did not activate ERK5. ERK5 thus represents a divergence in the signaling pathways activated by these two agents that bind to the Na+,K+-ATPase. Cycloheximide, okadaic acid, and sodium orthovandate did not mimic the effect of palytoxin on ERK5. These results indicate that the stimulation of ERK5 by palytoxin is not simply due to inhibition of protein synthesis or inhibition of serine/threonine or tyrosine phosphatases. Therefore, the mechanism by which palytoxin activates ERK5 differs from that by which it activates ERK1/2, JNK, and p38. Finally, studies that used pharmacological inhibitors and shRNA to block ERK5 action indicate that ERK5 contributes to palytoxin-stimulated c-Fos gene expression. These results suggest that ERK5 can act as an alternative mediator for transmitting diverse tumor promoter-stimulated signals.

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“…An increased metabolism of arachidonic acid and the production of eicosanoids has long been recognised as a cellular response to PlTX in different cells, such as rat liver cells, mouse clavarie, mouse 3T3 fibroblasts (Levine and Fujiki, 1985;Lazzaro et al, 1987;Miura et al, 2006). This response could be induced by some isoforms of Ca 2+ -stimulated phospholipase A 2 , that would be activated in cells exposed to PlTX and catalyses the hydrolysis of phosphatidylinositols (Habermann and Laux, 1986).…”

Section: Mechanistic Considerationsmentioning

confidence: 99%

“…This response could be induced by some isoforms of Ca 2+ -stimulated phospholipase A 2 , that would be activated in cells exposed to PlTX and catalyses the hydrolysis of phosphatidylinositols (Habermann and Laux, 1986). The arachidonic acid released from membrane phospholipids would then be metabolised to different prostaglandins (Lazzaro et al, 1987;Nagase and Karaki, 1987;Miura et al, 2006). The increased release of prostaglandin from the endothelium and smooth muscle cells has been shown to determine norepinephrine release and contraction of the rabbit aortas (Nagase and Karaki, EFSA Journal 2009;7(12):1393.…”

Section: Mechanistic Considerationsmentioning

confidence: 99%

Scientific Opinion on marine biotoxins in shellfish - Palytoxin group

2009

EFSA Journal

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The EFSA Panel on Contaminants in the Food Chain (CONTAM Panel) assessed the risks to human health related to the presence of palytoxin (PlTX)-group toxins in shellfish. PlTX-group toxins have mainly been detected in soft corals of the genus Palythoa and in algae of the genus Ostreopsis. Blooms of Ostreopsis spp. have recently been reported in some European countries. Occurrence of Ostreopsis spp. may result in contamination of shellfish intended for human consumption. Currently there are no regulations on PlTX-group toxins in shellfish, either in the European Union (EU), or in other regions of the world. The toxicological database of PlTX-group toxins is limited, comprising only acute toxicity studies for PlTX and ostreocin-D via several routes of administration in various animal species. The oral route was least sensitive. Acute toxicity and deaths have been reported from human outbreaks, but there are no reliable quantitative data on acute toxicity in humans. In view of the acute toxicity and the lack of chronic toxicity data for PlTX-group toxins, the CONTAM Panel was only able to derive an oral acute reference dose (ARfD) of 0.2 µg/kg b.w. for the sum of PlTX and its analogue ostreocin-D. In order for a 60 kg adult to avoid exceeding the ARfD a 400 g portion of shellfish meat should not contain more than 12 µg of the sum of PlTX and ostreocin-D, corresponding to 30 µg/kg shellfish meat. The mouse bioassay (MBA) has been used to detect PlTX-group toxins, but cell based assays have been developed as alternative. However, positive results require confirmation by chemical methods. High performance liquid chromatography-fluorescence detection (HPLC-FLD) and liquid chromatography-tandem mass spectrometry (LC-MS/MS) methods can be valuable tools for the determination, but method optimisation and validation as well as the development of certified reference materials and standards are necessary. KEY WORDSMarine biotoxins, palytoxin (PlTX)-toxin group toxins, shellfish, mussels, sea urchins, mouse bioassay (MBA), acute reference dose, portion size, methods of analysis, human health, risk assessment. PlTX-group toxins are complex polyhydroxylated compounds with both lipophilic and hydrophilic areas. At least 8 different PlTX analogues are known: PlTX, ostreocin-D, ovatoxin-A, homopalytoxin, bishomopalytoxin, neopalytoxin, deopalytoxin and 42-hydroxypalytoxin, but only for PlTX and ostreocin-D the chemical structure has been characterised. The occurrence data reported by European countries were limited and comprised only PlTX and ovatoxin-A in mussels and sea urchins. Currently there are no regulations on PlTX-group toxins in shellfish, either in the European Union (EU), or in other regions of the world.Signs and symptoms of PlTX-group toxins intoxication are not well-defined, but include myalgia and weakness, possibly accompanied by fever, nausea and vomiting. Fatalities appear to be rare although there are reports of severe cases, in which patients died after about 15 hours.The toxicological database is limit...

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Enhancement of Transformed Foci and Induction of Prostaglandins in Balb/c 3T3 Cells by Palytoxin: In Vitro Model Reproduces Carcinogenic Responses in Animal Models Regarding the Inhibitory Effect of Indomethacin and Reversal of Indomethacin's Effect by Exogenous Prostaglandins

Cited by 11 publications

References 31 publications

Modulation of protein kinase signaling cascades by palytoxin

Modulation of protein kinase signaling cascades by palytoxin

Extracellular signal regulated kinase 5 mediates signals triggered by the novel tumor promoter palytoxin

Scientific Opinion on marine biotoxins in shellfish - Palytoxin group

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