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ToxSci Advance Access published online on April 26, 2006
Toxicological Sciences, doi:10.1093/toxsci/kfj213
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© The Author 2006. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received March 3, 2006
Accepted April 13, 2006

Carcinogenicity

Ochratoxin A: Apoptosis and Aberrant Exit from Mitosis due to Perturbation of Microtubule Dynamics?

Eva Rached 1, Erika Pfeiffer 2, Wolfgang Dekant 1 *, and Angela Mally 1

1 Department of Toxicology, University of Würzburg, Germany
2 Institute of Applied Biosciences, Section of Food Chemistry and Toxicology, University of Karlsruhe, Germany

* To whom correspondence should be addressed.
Wolfgang Dekant, E-mail: dekant{at}toxi.uni-wuerzburg.de


  Abstract

Ochratoxin A (OTA) is a potent nephrotoxin and causes high incidences of renal tumors in rodents. The molecular events leading to tumor formation by OTA are not well defined. Early pathological changes observed in kidneys of rats treated with OTA in vivo include frequent mitotic and abnormally enlarged cells, detachment of tubule cells and apoptosis within the S3 segment of the proximal tubule, suggesting that OTA may interfere with molecules involved in the regulation of cell division and apoptosis. In this study, treatment of immortalized human kidney epithelial cells (IHKE) with OTA (0 - 50 µM) resulted in a time- and dose-dependent increase in apoptosis and activation of JNK. At the same time, OTA blocked metaphase/anaphase transition and led to the formation of aberrant mitotic figures and giant cells with abnormally enlarged and/or multiple nuclei, sometimes still connected by chromatin bridges. Immunostaining of the mitotic apparatus using an {alpha}-tubulin antibody revealed defects in spindle formation. In addition, OTA inhibited microtubule assembly in a concentration-dependent manner in a cell free in vitro assay. Interestingly, treatment with OTA also resulted in activation of the transcription factor NF{kappa}B, which has recently been shown to promote cell survival during mitotic cell cycle arrest. Based on these observations, we hypothesize that the mechanism by which OTA promotes tumor formation involves interference with microtubuli dynamics and mitotic spindle formation, resulting in apoptosis or - in the presence of survival signals such as stimulation of the NF{kappa}B pathway - premature exit from mitosis. Aberrant exit from mitosis resulting in blocked or asymmetric cell division may favor the occurence of cytogenetic abnormalities and may therefore play a critical role in renal tumor formation by OTA.

Keywords: Ochratoxin A; carcinogenicity; apoptosis; mitosis; microtubule.
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