Modulation of protein kinase signaling cascades by palytoxin

Wattenberg, Elizabeth V.

doi:10.1016/j.toxicon.2010.11.003

Cited by 20 publications

(20 citation statements)

References 86 publications

(128 reference statements)

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“…It has been well established that mitogen-activated protein kinases can mediate palytoxin-stimulated signalling [28]. In our experimental model, both p38 MAPK and JNK were indeed phosphorylated upon exposure of macrophages to PLTX or to the OSTRTX extract (Figure 8A).…”

Section: Discussionsupporting

confidence: 53%

Palytoxin and an Ostreopsis Toxin Extract Increase the Levels of mRNAs Encoding Inflammation-Related Proteins in Human Macrophages via p38 MAPK and NF-κB

et al. 2012

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BackgroundPalytoxin and, likely, its analogues produced by the dinoflagellate genus Ostreopsis, represent a class of non-proteinaceous compounds displaying high toxicity in animals. Owing to the wide distribution and the poisonous effects of these toxins in humans, their chemistry and mechanism of action have generated a growing scientific interest. Depending on the exposure route, palytoxin and its Ostreopsis analogues may cause several adverse effects on human health, including acute inflammatory reactions which seem more typical of cutaneous and inhalation contact. These observations have led us to hypothesize that these toxins may activate pro-inflammatory signalling cascades.Methodology and Principal FindingsHere we demonstrate that palytoxin and a semi-purified Ostreopsis cf. ovata toxin extract obtained from a cultured strain isolated in the NW Adriatic Sea and containing a putative palytoxin and all the ovatoxins so far known – including the recently identified ovatoxin-f – significantly increase the levels of mRNAs encoding inflammation-related proteins in immune cells, i.e. monocyte-derived human macrophages, as assessed by Real-Time PCR analysis. Western immunoblot and electrophoretic mobility shift assays revealed that nuclear transcription factor -κB (NF-κB) is activated in cells exposed to toxins in coincidence with reduced levels of the inhibitory protein IκB-α. Moreover, Mitogen-Activated Protein Kinases (MAPK) were phosphorylated in response to palytoxin, as also reported by others, and to the Ostreopsis toxin extract, as shown here for the first time. By using specific chemical inhibitors, the involvement of NF-κB and p38 MAPK in the toxin-induced transcription and accumulation of Cycloxigenase-2, Tumor Necrosis Factor-α, and Interleukin-8 transcripts has been demonstrated.Conclusions and SignificanceThe identification of specific molecular targets of palytoxin and its Ostreopsis analogues, besides contributing to expand the still limited knowledge of the intracellular signalling cascades affected by these toxins, may have important implications in setting up focused pharmacological interventions, replacing currently used symptomatic treatments.

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Section: Discussionsupporting

confidence: 53%

Palytoxin and an Ostreopsis Toxin Extract Increase the Levels of mRNAs Encoding Inflammation-Related Proteins in Human Macrophages via p38 MAPK and NF-κB

et al. 2012

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“…PTX stimulates JNK activation through a pathway that involves ion flux [6]. Initial studies showed that PTX affects JNK activation through a mechanism that involves sodium influx [17].…”

Section: Discussionmentioning

confidence: 99%

“…In contrast to most cytotoxins, PTX exerts its activity extracellularly by altering ion equilibria in biological systems [4]. PTX displays an extraordinary level of cytotoxic activity on a variety of cell lines and it develops a wide spectrum of pharmacological effects such as cellular disruption, binding of the toxin to its receptor [5], and modulation of protein kinase signalling cascades [6]. Other studies highlight the cytoskeleton as an early target for the toxic effects of PTX and its analog ostreocin-D on intestinal [7] and neuroblastoma cells [8].…”

Section: Introductionmentioning

confidence: 99%

“…As a consequence of alterations in ion gradients, many modifications of cytosolic proteins occur. Thus, PTX causes modulation of mitogen-activated protein kinase (MAPK) cascades [6] and stimulates JNK activation in mouse 3T3 fibroblasts [17]. It was suggested that PTX is also capable of perturbing growth regulatory systems by down-regulation of epidermal growth factor (EGF) binding through a protein kinase C-independent pathway.…”

Section: Introductionmentioning

confidence: 99%

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Head and neck cancer cells and xenografts are very sensitive to palytoxin: decrease of c-jun n-terminale kinase-3 expression enhances palytoxin toxicity

et al. 2013

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ObjectivesPalytoxin (PTX), a marine toxin isolated from the Cnidaria (zooanthid) Palythoa caribaeorum is one of the most potent non-protein substances known. It is a very complex molecule that presents both lipophilic and hydrophilic areas. The effect of PTX was investigated in a series of experiments conducted in head and neck squamous cell carcinoma (HNSCC) cell lines and xenografts.Materials and methodsCell viability, and gene expression of the sodium/potassium-transporting ATPase subumit alpha1 (ATP1AL1) and GAPDH were analyzed in HNSCC cells and normal epithelial cells after treatment with PTX using cytotoxicity-, clonogenic-, and enzyme inhibitor assays as well as RT-PCR and Northern Blotting. For xenograft experiments severe combined immunodeficient (SCID) mice were used to analyze tumor regression. The data were statistically analyzed using One-Way Annova (SPSS vs20).ResultsSignificant toxic effects were observed in tumor cells treated with PTX (LD50 of 1.5 to 3.5 ng/ml) in contrast to normal cells. In tumor cells PTX affected both the release of LDH and the expression of the sodium/potassium-transporting ATPase subunit alpha1 gene suggesting loss of cellular integrity, primarily of the plasma membrane. Furthermore, strong repression of the c-Jun N-terminal kinase 3 (JNK3) mRNA expression was found in carcinoma cells which correlated with enhanced toxicity of PTX suggesting an essential role of the mitogen activated protein kinase (MAPK)/JNK signalling cascades pathway in the mechanisms of HNSCC cell resistance to PTX. In mice inoculated with carcinoma cells, injections of PTX into the xenografted tumors resulted within 24 days in extensive tumor destruction in 75% of the treated animals (LD50 of 68 ng/kg to 83 ng/kg) while no tumor regression occurred in control animals.ConclusionsThese results clearly provide evidence that PTX possesses preferential toxicity for head and neck carcinoma cells and therefore it is worth further studying its impact which may extend our knowledge of the biology of head and neck cancer.

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“…Conversely, palytoxin has been identified as a tumour promoter by disrupting the regulation of cellular signalling cascades [132].…”

Section: The Role Of Cnidarians Venoms In Drug Discoverymentioning

confidence: 99%

Evolution and diversification of the cnidarian venom system

Jouiaei¹

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The phylum Cnidaria (corals, sea pens, sea anemones, jellyfish and hydroids) is the oldest venomous animal lineage (~750 million years old), making it an ideal phylum to understand the origin and diversification of venom. Cnidarians are characterised by specialised cellular structures called cnidae, which they utilise to inject mixtures of bioactive compounds or venom for predation and defence. In recent years cnidarian venoms have begun to be investigated as a potential source of novel bioactive therapeutics. However, in comparison with several venomous lineages that are relatively younger, such as snakes, cone snails and spiders, the diversification and molecular evolutionary regimes of toxins encoded by these fascinating and ancient animals remain poorly understood.The first experimental part of this thesis (Chapter 2) is comprised of the phylogenetic and molecular evolutionary histories of pharmacologically characterised cnidarian toxin families. These include peptide neurotoxins (voltage-gated Na + and K + channel-targeting toxins: NaTxs and KTxs, respectively), pore-forming toxins (actinoporins, aerolysin-related toxins, and jellyfish toxins) and small cysteine-rich peptides (SCRiPs). Our analyses show that most cnidarian toxins remain conserved under the strong influence of negative selection. A deeper analysis of the molecular evolutionary histories of neurotoxins demonstrates that type III KTxs have evolved from NaTxs under the regime of positive selection and likely represent a unique evolutionary innovation of the Actinioidea lineage. We also identify a few functionally important sites in other classes of neurotoxins and pore-forming toxins that experienced episodic adaptation. In addition, we describe the first family of neurotoxic peptides (SCRiPs) in reef-building corals, Acropora millepora, that are likely involved in the envenoming function.The third chapter describes the development of a novel venom extraction technique which is rapid, repeatable and cost effective. This technique involves using ethanol to both induce cnidae discharge and to recover venom contents in one step. Our model species is the notorious Australian box jellyfish (Chironex fleckeri) which has a notable impact on public health. By using the complementary approaches of transcriptomics, proteomics, mass spectrometry, histology, and scanning electron microscopy, this study compares the proteome profile of the new ethanol recovery based method to a previously reported protocol, based upon density purified intact cnidae and pressure induced disruption. This work not only results in the expansion of identified Australian box jellyfish venom components but also illustrates that ethanol extraction method could greatly augment future cnidarian venom proteomics research efforts.The forth chapter is constituted by previously described venom extraction technique, ethanolinduced discharge of cnidae, to rapidly and efficiently characterise venom components of the Jelly Blubber or Blue Blubber Jellyfish, Catostylus mosaicus. By us...

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Modulation of protein kinase signaling cascades by palytoxin

Cited by 20 publications

References 86 publications

Palytoxin and an Ostreopsis Toxin Extract Increase the Levels of mRNAs Encoding Inflammation-Related Proteins in Human Macrophages via p38 MAPK and NF-κB

Palytoxin and an Ostreopsis Toxin Extract Increase the Levels of mRNAs Encoding Inflammation-Related Proteins in Human Macrophages via p38 MAPK and NF-κB

Head and neck cancer cells and xenografts are very sensitive to palytoxin: decrease of c-jun n-terminale kinase-3 expression enhances palytoxin toxicity

Evolution and diversification of the cnidarian venom system

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