A Journey Through Mitogen-Activated Protein Kinase and Ochratoxin A Interactions

Rumora, Lada; Grubišić, Tihana Žanić

doi:10.2478/10004-1254-60-2009-1969

Cited by 21 publications

(9 citation statements)

References 57 publications

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“…In summary, these studies showed that OTA is nephrotoxic, hepatotoxic, neurotoxic, teratogenic and immunotoxic in various animals and in vitro , with renal toxicity and carcinogenesis being the key adverse effects. Many studies of OTA from the last decade support a non-DNA-reactive genotoxic mechanism, which involves different epigenetic mechanisms mainly related to oxidative stress, compensatory cell proliferation and disruption of cell signaling and division, and these publications have been thoroughly reviewed by various authors [ 6 , 63 , 70 , 113 , 119 , 139 , 140 ]. However, a direct genotoxic mechanism involving OTA bioactivation and DNA adduct formation is also still discussed [ 115 , 120 ] and this mechanism is also consistent with some in vivo gene expressionresults [ 113 ].…”

Section: Differential Toxicity Of Ochratoxin Group Membersmentioning

confidence: 99%

Comparative Ochratoxin Toxicity: A Review of the Available Data

Heussner

Bingle

2015

Toxins

266

160

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Ochratoxins are a group of mycotoxins produced by a variety of moulds. Ochratoxin A (OTA), the most prominent member of this toxin family, was first described by van der Merwe et al. in Nature in 1965. Dietary exposure to OTA represents a serious health issue and has been associated with several human and animal diseases including poultry ochratoxicosis, porcine nephropathy, human endemic nephropathies and urinary tract tumours in humans. More than 30 years ago, OTA was shown to be carcinogenic in rodents and since then extensive research has been performed in order to investigate its mode of action, however, this is still under debate. OTA is regarded as the most toxic family member, however, other ochratoxins or their metabolites and, in particular, ochratoxin mixtures or combinations with other mycotoxins may represent serious threats to human and animal health. This review summarises and evaluates current knowledge about the differential and comparative toxicity of the ochratoxin group.

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Section: Differential Toxicity Of Ochratoxin Group Membersmentioning

confidence: 99%

Comparative Ochratoxin Toxicity: A Review of the Available Data

Heussner

Bingle

2015

Toxins

266

160

View full text Add to dashboard Cite

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“…Furthermore, it has been reported that OTA might regulate cell fate via stimulating Mitogen Activated Protein Kinase (MAPK) family members, including ERK1/2, JNK, and p38 MAPK4111213. MAPKs are evolutionarily conserved serine/threonine kinases that respond to various chemical and physical stresses and play essential roles in cell survival and adaptation14.…”

mentioning

confidence: 99%

Apoptosis Signal-regulating Kinase 1 promotes Ochratoxin A-induced renal cytotoxicity

Liang

Shen

Zhang

et al. 2015

Sci Rep

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Oxidative stress and apoptosis are involved in Ochratoxin A (OTA)-induced renal cytotoxicity. Apoptosis signal-regulating kinase 1 (ASK1) is a Mitogen-Activated Protein Kinase Kinase Kinase (MAPKKK, MAP3K) family member that plays an important role in oxidative stress-induced cell apoptosis. In this study, we performed RNA interference of ASK1 in HEK293 cells and employed an iTRAQ-based quantitative proteomics approach to globally investigate the regulatory mechanism of ASK1 in OTA-induced renal cytotoxicity. Our results showed that ASK1 knockdown alleviated OTA-induced ROS generation and Δψm loss and thus desensitized the cells to OTA-induced apoptosis. We identified 33 and 24 differentially expressed proteins upon OTA treatment in scrambled and ASK1 knockdown cells, respectively. Pathway classification and analysis revealed that ASK1 participated in OTA-induced inhibition of mRNA splicing, nucleotide metabolism, the cell cycle, DNA repair, and the activation of lipid metabolism. We concluded that ASK1 plays an essential role in promoting OTA-induced renal cytotoxicity.

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“…Moreover, it has been reported that mere activation of p38 and JNK may not be necessary for apoptosis under all conditions, but concurrent inhibition of ERK1/2 is also a critical factor [38]. Thus, a dynamic balance between ERK pathway and p38 and JNK pathways determines whether a cell will survive or undergo apoptosis [39] which has been observed to be shifting towards p38 and JNK, leading to apoptosis in mouse skin following dermal exposure to OTA.…”

Section: Discussionmentioning

confidence: 99%

Topical Application of Ochratoxin A Causes DNA Damage and Tumor Initiation in Mouse Skin

et al. 2012

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Skin cancer is one of the most common forms of cancer and 2–3 million new cases are being diagnosed globally each year. Along with UV rays, environmental pollutants/chemicals including mycotoxins, contaminants of various foods and feed stuffs, could be one of the aetiological factors of skin cancer. In the present study, we evaluated the DNA damaging potential and dermal carcinogenicity of a mycotoxin, ochratoxin A (OTA), with the rationale that dermal exposure to OTA in workers may occur during their involvement in pre and post harvest stages of agriculture. A single topical application of OTA (20–80 µg/mouse) resulted in significant DNA damage along with elevated γ-H2AX level in skin. Alteration in oxidative stress markers such as lipid peroxidation, protein carbonyl, glutathione content and antioxidant enzymes was observed in a dose (20–80 µg/mouse) and time-dependent (12–72 h) manner. The oxidative stress was further emphasized by the suppression of Nrf2 translocation to nucleus following a single topical application of OTA (80 µg/mouse) after 24 h. OTA (80 µg/mouse) application for 12–72 h caused significant enhancement in- (a) reactive oxygen species generation, (b) activation of ERK1/2, p38 and JNK MAPKs, (c) cell cycle arrest at G0/G1 phase (37–67%), (d) induction of apoptosis (2.0–11.0 fold), (e) expression of p53, p21/waf1, (f) Bax/Bcl-2 ratio, (g) cytochrome c level, (h) activities of caspase 9 (1.2–1.8 fold) and 3 (1.7–2.2 fold) as well as poly ADP ribose polymerase cleavage. In a two-stage mouse skin tumorigenesis protocol, it was observed that a single topical application of OTA (80 µg/mouse) followed by twice weekly application of 12-O-tetradecanoylphorbol-13-acetate for 24 week leads to tumor formation. These results suggest that OTA has skin tumor initiating property which may be related to oxidative stress, MAPKs signaling and DNA damage.

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A Journey Through Mitogen-Activated Protein Kinase and Ochratoxin A Interactions

Cited by 21 publications

References 57 publications

Comparative Ochratoxin Toxicity: A Review of the Available Data

Comparative Ochratoxin Toxicity: A Review of the Available Data

Apoptosis Signal-regulating Kinase 1 promotes Ochratoxin A-induced renal cytotoxicity

Topical Application of Ochratoxin A Causes DNA Damage and Tumor Initiation in Mouse Skin

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