ToxSci Advance Access originally published online on November 21, 2006
Toxicological Sciences 2007 95(2):427-435; doi:10.1093/toxsci/kfl167
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Azaspiracid-1 Alters the E-cadherin Pool in Epithelial Cells
* Dipartimento di Scienze Biomediche, Università di Modena e Reggio Emilia, I-41100 Modena, Italy
Biotoxin Chemistry, Marine Environment and Food Safety Services, Marine Institute, Rinville, Oranmore, County Galway, Ireland
1 To whom correspondence should be addressed Gian Paolo Rossini, Dipartimento di Scienze Biomediche, Università di Modena e Reggio Emilia, Via G. Campi 287, I-41100 Modena, Italy. Fax: +39 059-205-5410. E-mail: rossini.gianpaolo{at}unimore.it.
Received August 23, 2006; accepted November 7, 2006
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Abstract |
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Azaspiracids cause severe damages in the epithelium of several organs. In this study we have investigated the effects of azaspiracid-1 (AZA-1) on two epithelial cell lines. Nanomolar concentrations of AZA-1 reduced MCF-7 cell proliferation and impaired cell-cell adhesion. AZA-1 altered the cellular pool of the adhesion molecule E-cadherin by inducing a dose- and time-dependent accumulation of an E-cadherin fragment (E-cadherin–related antigen [ECRA100]), with a concentration inducing the half-maximal effect (EC50) of 0.47nM. The immunological characterization of ECRA100 revealed that it consists of an E-cadherin molecule lacking the intracellular domain, and these data showed that the effect induced by AZA-1 in MCF-7 cells is undistinguishable from that induced by yessotoxin (YTX) in the same experimental system. A comparison of toxin effects in MCF-7 and Caco 2 cells confirmed that the effects induced by AZA-1 and YTX are undistinguishable in these cells. Treatment of fibroblasts with AZA-1 did not affect the cellular pool of N-cadherin showing that the toxin effect is cadherin-specific. A comparison of the effects induced by AZA-1, YTX, and okadaic acid on F-actin and E-cadherin in MCF-7 and Caco 2 cells showed that 1nM AZA-1 did not cause significant changes in F-actin and that accumulation of ECRA100 did not correlate with decreased levels of F-actin under our experimental conditions. Matching our results with those available in literature, we notice that, when molecular effects induced by AZA-1 and YTX have been studied in the same in vitro systems, experimental data show that they are undistinguishable in terms of sensitive cellular parameters, effective doses, and kinetics of responses in several cell lines. The possibility that azaspiracids and YTXs might share their molecular mechanism(s) of action in defined biological settings should be considered.
Key Words: azaspiracid; yessotoxin; E-cadherin; N-cadherin; epithelial cells; okadaic acid.