Self-Association of Okadaic Acid: Structural and Pharmacological Significance

Cruz, Patricia G.; Norte, Manuel; Creus, Alberto Hernández; Fernández, José J.; Daranas, Antonio Hernández

doi:10.3390/md11061866

Cited by 14 publications

(6 citation statements)

References 27 publications

(33 reference statements)

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“…In contrast, DTX-3 is inactive against these proteins if not hydrolyzed [ 21 ]. The PP inhibition leads to a dramatic increase of phosphorylation of a number of proteins resulting in important cell alterations, and this is the main reason why OA is an invaluable pharmacological tool in the study of cellular signaling [ 22 ]. In addition, because of this property, it was suspected that this toxin is much more than a simple diarrheic agent.…”

Section: Introductionmentioning

confidence: 99%

Okadaic Acid: More than a Diarrheic Toxin

et al. 2013

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Okadaic acid (OA) is one of the most frequent and worldwide distributed marine toxins. It is easily accumulated by shellfish, mainly bivalve mollusks and fish, and, subsequently, can be consumed by humans causing alimentary intoxications. OA is the main representative diarrheic shellfish poisoning (DSP) toxin and its ingestion induces gastrointestinal symptoms, although it is not considered lethal. At the molecular level, OA is a specific inhibitor of several types of serine/threonine protein phosphatases and a tumor promoter in animal carcinogenesis experiments. In the last few decades, the potential toxic effects of OA, beyond its role as a DSP toxin, have been investigated in a number of studies. Alterations in DNA and cellular components, as well as effects on immune and nervous system, and even on embryonic development, have been increasingly reported. In this manuscript, results from all these studies are compiled and reviewed to clarify the role of this toxin not only as a DSP inductor but also as cause of alterations at the cellular and molecular levels, and to highlight the relevance of biomonitoring its effects on human health. Despite further investigations are required to elucidate OA mechanisms of action, toxicokinetics, and harmful effects, there are enough evidences illustrating its toxicity, not related to DSP induction, and, consequently, supporting a revision of the current regulation on OA levels in food.

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Section: Introductionmentioning

confidence: 99%

Okadaic Acid: More than a Diarrheic Toxin

et al. 2013

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“…In addition, PP2A can be activated via oxidative stress such as high ROS generation to participate in many signaling pathways of mammalian cells [42][43][44][45][46][47]. In fact, our mitochondrial fractionation experiment showed that TRIP-Br1 translocation into mitochondria was blocked when cells were treated with okadaic acid, a PP2A specific inhibitor (Figure 3C) [48,49]. Our hypothesis was further tested in U2OS 4.3 osteosarcoma cells, in which TRIP-Br1 expression could be induced by doxycycline [50].…”

Section: Mitochondrial Translocation Of Trip-br1 Via Dephosphorylatio...mentioning

confidence: 75%

Inhibitory role of TRIP-Br1 oncoprotein in anticancer drug-mediated programmed cell death via mitophagy activation

Jung¹,

Myagmarjav²,

Jo³

et al. 2022

Int. J. Biol. Sci.

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Chemotherapy has been widely used as a clinical treatment for cancer over the years. However, its effectiveness is limited because of resistance of cancer cells to programmed cell death (PCD) after treatment with anticancer drugs. To elucidate the resistance mechanism, we initially focused on cancer cell-specific mitophagy, an autophagic degradation of damaged mitochondria. This is because mitophagy has been reported to provide cancer cells with high resistance to anticancer drugs. Our data showed that TRIP-Br1 oncoprotein level was greatly increased in the mitochondria of breast cancer cells after treatment with various anticancer drugs including staurosporine (STS), the main focus of this study. STS treatment increased cellular ROS generation in cancer cells, which triggered mitochondrial translocation of TRIP-Br1 from the cytosol via dephosphorylation of TRIP-Br1 by protein phosphatase 2A (PP2A). Up-regulated mitochondrial TRIP-Br1 suppressed cellular ROS levels. In addition, TRIP-Br1 rapidly removed STS-mediated damaged mitochondria by activating mitophagy. It eventually suppressed STS-mediated PCD via degradation of VDACI, TOMM20, and TIMM23 mitochondrial membrane proteins. TRIP-Br1 enhanced mitophagy by increasing expression levels of two crucial lysosomal proteases, cathepsins B and D. In conclusion, TRIP-Br1 can suppress the sensitivity of breast cancer cells to anticancer drugs by activating autophagy/mitophagy, eventually promoting cancer cell survival.

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“…Recent reports point to modulation of neurotransmitters that regulate intestinal mobility, along with water and electrolyte secretion as the cause of DSP syndrome (Valdiglesias et al, 2013;Louzao et al, 2015). Protein phosphatases modulate cell signaling pathways so their inhibition by OA and DTXs renders them as an important tool in medical and physiological studies (Meštrović and Pavela-Vrančič, 2003;Cruz et al, 2013;Valdiglesias et al, 2013). In addition, chronic exposure to OA can induce cytotoxicity, neurotoxicity, immunotoxicity, embriotoxicity, genotoxicity and cancer promotion as reviewed by Vilariño et al (2018) and Fu et al (2019).…”

Section: Toxic Bioactive Metabolites Frommentioning

confidence: 99%

High Value Phycotoxins From the Dinoflagellate Prorocentrum

et al. 2021

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Marine dinoflagellates produce chemically diverse compounds, with a wide range of biological activity (antimicrobial, anticancer, treatment of neurodegenerative disease along with use as biomedical research tools). Chemical diversity is highlighted by their production of molecules such as the saxitoxin family of alkaloids (C10H17N7O4 – 299 g/mol) to the amphipathic maitotoxin (C164H256O68S2Na2 – 3,422 g/mol), representing one of the largest and most complex secondary metabolites characterized. Dinoflagellates, are most well-known for the production of red tides which are frequently toxic, including okadaic acid and related dinophysistoxins, which are tumor promoters. The mode of action for these phycotoxins, is by specific inhibition of protein phosphatases, enzymes essential in regulation of many cellular processes. Hence, these compounds are being used for vital cell regulation studies. However, the availability of useful amounts of these compounds has restricted research. Chemical synthesis of some compounds such as okadaic acid has been investigated, but the complexity of the molecule resulted in many lengthy steps and achieved only a poor yield. The use of naturally occurring phytoplankton has been investigated as a potential source of these compounds, but it has been shown to be unreliable and impractical. The most practical option is large scale culture with down-stream processing/purification which requires specialist facilities and expertise. This review, describes the biotechnological potential of these organisms and the challenges to achieve useful yields of high quality phycotoxins using Prorocentrum spp. as an example to produce okadaic acid.

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Self-Association of Okadaic Acid: Structural and Pharmacological Significance

Cited by 14 publications

References 27 publications

Okadaic Acid: More than a Diarrheic Toxin

Okadaic Acid: More than a Diarrheic Toxin

Inhibitory role of TRIP-Br1 oncoprotein in anticancer drug-mediated programmed cell death via mitophagy activation

High Value Phycotoxins From the Dinoflagellate Prorocentrum

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