Ochratoxin A affects COS cell adhesion and signaling

Scibelli, Antonio; Tafuri, Simona; Ferrante, Maria Carmela; Alimenti, Elena; Naso, Barbara; Lucisano, A.; Staiano, Norma; Morte, Renata Della

doi:10.1016/s0041-008x(03)00300-4

Cited by 11 publications

(7 citation statements)

References 38 publications

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“…Earlier studies concerning OTA found this mycotoxin to enhance caspase activities in kidney cells of monkeys (Scibelli et al 2003) or rat , as well as in human peripheral blood lymphocytes (Assaf et al 2004) in concentrations comparable to those used in this study.…”

Section: Discussionsupporting

confidence: 77%

Characterization of ochratoxin A-induced apoptosis in primary rat hepatocytes

et al. 2009

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The main target organ of the mycotoxin ochratoxin A (OTA) in mammals is the kidney but OTA has also been shown to be hepatotoxic in rats and to induce tumors in mouse liver. Even at very low concentrations, OTA causes perturbations of cellular signaling pathways as well as enhanced apoptosis. OTA has been extensively studied in kidney cell systems. Since this substance also affects liver health, we focused our work on apoptosis-related events induced by OTA in primary rat hepatocytes. We performed pathway-specific polymerase chain reaction arrays to assess the expression of genes involved in apoptosis. Treatment with 1 microM OTA for 24 h caused marked changes in apoptosis-related gene expression. Genes as apaf1, bad, caspase 7, polb (DNA polymerase beta, performs base excision repair), and p53, which are marker genes for DNA damage, were upregulated. FAS and faslg were also markedly induced by treatment with OTA. Treatment of hepatocytes with OTA led to a concentration-dependent inhibition of protein biosynthesis. Apoptosis-inducing factor was released from mitochondria following OTA treatment; the mycotoxin induced the activity of caspases 8, 9, and 3/7 and caused chromatin condensation and fragmentation. Caspase inhibition led to a significant but not complete reduction of OTA-induced apoptosis. Our data suggest that not only OTA leads to p53-dependent apoptosis in rat hepatocytes but it also hints to other mechanisms, independent of caspase activation or protein biosynthesis, being involved.

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Section: Discussionsupporting

confidence: 77%

Characterization of ochratoxin A-induced apoptosis in primary rat hepatocytes

et al. 2009

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“…The balance between these processes may determine cell fate, tipping cells toward proliferation and eventually malignant cell transformation (Mally and Dekant 2009). Earlier studies concerning OTA found this mycotoxin to enhance caspase activities in kidney cells of monkeys (Scibelli et al 2003) or rats , as well as in cultured primary rat hepatocytes (Chopra et al 2010). In this study, OTA led to an up to 2.85-fold increase of executioner *** *** *** *** Fig.…”

Section: Effect Of Silibinin On Ota Cytotoxicitysupporting

confidence: 52%

Silibinin pretreatment protects against Ochratoxin A-mediated apoptosis in primary rat hepatocytes

Essid

Petzinger

2011

Mycotox Res

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The inhibitory effect of silibinin on ochratoxin A (OTA)-mediated apoptosis on primary rat hepatocytes was investigated. Rat hepatocytes were prepared by two different methods: the classical enzymatic digestion method by collagenase perfusion and a new EDTA-perfusion method. The EDTA-perfusion method yielded hepatocytes, which were stably cultivated without DNA fragmentation for up to 96 h, whereas the collagenase-prepared hepatocytes showed apoptosis events as early as from the start of preparation even in the absence of OTA. Treatment with 12.5 μmol/l OTA of cultured hepatocytes prepared under ETDA perfusion developed DNA-laddering after 24-36 h. Lipopolysaccharide (LPS) of 0.1 up to 12.5 μg/ml showed no apoptotic DNA-effects under these conditions. A low concentration of 26 μmol/l silibinin given prior to OTA slightly prevented OTA-mediated DNA-laddering, whereas a five times higher concentration of silibinin (130 μmol/l) completely inhibited OTA-mediated apoptosis. Under the same conditions, caspase-3 activity in hepatocytes increased in a time-dependent manner under OTA exposure within 12-24 h but was blocked by 130 μmol/l silibinin. In contrast, LPS incubation for 12 and 24 h did not alter caspase-3 activity. To measure viability of OTA-/LPS-treated hepatocytes, the MTT-test and Live/Dead kit were applied. The results demonstrated that the used OTA concentration of 12.5 μmol/l only moderately decreased viability for up to 24 h but showed cytotoxic effects depending on longer incubation times (≥36 h). In contrast, LPS up to 12.5 μg/ml exhibited no cytotoxic effects up to 48 h. In summary, our results showed contrasting effects on apoptosis in primary rat hepatocytes by OTA (produces apoptosis) versus LPS (produces no apoptosis), also depending on the method of hepatocyte preparation. Silibinin at 130 μmol/l showed significant hepatoprotective and antiapoptotic effects against OTA-mediated cell damage on cultured rat hepatocytes.

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“…In contrast, suppression of FAK with siRNA further increased the apoptotic effects of V + H -, suggesting that caspase-3 is an executioner caspase that mediates V + H --induced apoptosis. FAK and caspase-3 are also involved in anoikis in breast cancer [63] and COS cells [64]. Previously, we showed that caspase-1 and caspase-3 are involved in V + H --induced anoikis in fibroblasts [42].…”

Section: Discussionmentioning

confidence: 90%

An altered fibronectin matrix induces anoikis of human squamous cell carcinoma cells by suppressing integrin alpha v levels and phosphorylation of FAK and ERK

Kamarajan

Kapila

2007

Apoptosis

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Fibronectin regulates many cellular processes, including migration, proliferation, differentiation, and survival. Previously, we showed that squamous cell carcinoma (SCC) cell aggregates escape suspension-induced, p53-mediated anoikis by engaging in fibronectin-mediated survival signals through focal adhesion kinase (FAK). Here we report that an altered matrix, consisting of a mutated, nonfunctional high-affinity heparin-binding domain and the V region of fibronectin (V+H-), induced anoikis in human SCC cells; this response was blocked by inhibitors of caspase-8 and caspase-3. Anoikis was mediated by downregulation of integrin alpha v in a panel of SCC cells and was shown to be proteasome-dependent. Overexpression of integrin alpha v or FAK inhibited the increase in caspase-3 activation and apoptosis, whereas suppression of alpha v or FAK triggered a further significant increase in apoptosis, indicating that the apoptosis was mediated by suppression of integrin alpha v levels and dephosphorylation of FAK. Treatment with V+H- decreased the phosphorylation of extracellular signal-regulated kinase (ERK) 1 and 2, and direct activation of ERK by constitutively active MEK1, an ERK kinase, increased ERK1 and ERK2 phosphorylation and inhibited the increase in apoptosis induced by V+H-. ERK acted downstream from alpha v and FAK signals, since alpha v and FAK overexpression inhibited both the decrease in ERK phosphorylation and the increase in anoikis triggered by V+H-. These findings provide evidence that mutations in the high-affinity heparin-binding domain in association with the V region of fibronectin, or altered fibronectin matrices, induce anoikis in human SCC cells by modulating integrin alpha v-mediated phosphorylation of FAK and ERK.

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Ochratoxin A affects COS cell adhesion and signaling

Cited by 11 publications

References 38 publications

Characterization of ochratoxin A-induced apoptosis in primary rat hepatocytes

Characterization of ochratoxin A-induced apoptosis in primary rat hepatocytes

Silibinin pretreatment protects against Ochratoxin A-mediated apoptosis in primary rat hepatocytes

An altered fibronectin matrix induces anoikis of human squamous cell carcinoma cells by suppressing integrin alpha v levels and phosphorylation of FAK and ERK

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