Ochratoxin A: apoptosis and aberrant exit from mitosis due to perturbation of microtubule dynamics?
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 (IHKE) cells with OTA (0-50 microM) resulted in a time- and dose-dependent increase in apoptosis and activation of c-Jun N-terminal kinase. 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 nuclear factor kappa B (NFkappaB), 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 NFkappaB pathway-premature exit from mitosis. Aberrant exit from mitosis resulting in blocked or asymmetric cell division may favor the occurrence of cytogenetic abnormalities and may therefore play a critical role in renal tumor formation by OTA.
Rached
Eva
E
Department of Toxicology, University of Würzburg, Versbacher Strasse 9, 97078 Würzburg, Germany.
Pfeiffer
Erika
E
Dekant
Wolfgang
W
Mally
Angela
A
D017209:Apoptosis / Q000187:drug effects*; D002461:Cell Line, Transformed; D005455:Fluorescent Antibody Technique; D006801:Humans; D008870:Microtubules / Q000187:drug effects*; D008938:Mitosis / Q000187:drug effects*; D009183:Mycotoxins / Q000633:toxicity*; D009793:Ochratoxins / Q000633:toxicity*
D009183:Mycotoxins; D009793:Ochratoxins; C025589:ochratoxin A