Ochratoxin A: Apoptosis and aberrant exit from mitosis due to perturbation of microtubule dynamics?
Ochratoxin A: Apoptosis and aberrant exit from mitosis due to perturbation of microtubule dynamics?
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DOI：
10.1093/toxsci/kfj213
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发表时间：
2006-07-01
影响因子：
3.8
通讯作者：
Mally, Angela
中科院分区：
文献类型：
--
作者：
Rached, Eva;Pfeiffer, Erika;Mally, Angela
赭曲霉毒素A（OTA）是一种强有力的肾毒素，可导致啮齿动物肾肿瘤的高发病率。OTA导致肿瘤形成的分子事件尚未明确。在体内用OTA处理的大鼠肾脏中观察到的早期病理变化包括频繁的有丝分裂和异常增大的细胞、小管细胞的脱离以及近端小管S3段内的凋亡，这表明OTA可能干扰参与调节细胞分裂和凋亡的分子。在这项研究中，用OTA（0-50 μ M）处理永生化人肾上皮（IHKE）细胞导致细胞凋亡和c-Jun N-末端激酶活化的时间和剂量依赖性增加。同时，OTA阻断了中期/后期的转换，并导致异常的有丝分裂像和巨细胞的形成，这些巨细胞具有异常增大和/或多个核，有时仍通过染色质桥连接。使用α-微管蛋白抗体对有丝分裂器进行免疫染色显示纺锤体形成缺陷。此外，OTA在无细胞体外试验中以浓度依赖性方式抑制微管组装。有趣的是，用OTA处理还导致转录因子核因子κ B（NF κ B B）的激活，其最近被证明在有丝分裂细胞周期停滞期间促进细胞存活。基于这些观察结果，我们推测OTA促进肿瘤形成的机制涉及微管动力学和有丝分裂纺锤体形成的干扰，导致凋亡或在存在存活信号如刺激NF κ B通路的情况下过早退出有丝分裂。有丝分裂的异常退出导致细胞分裂受阻或不对称，可能有利于细胞遗传学异常的发生，因此可能在OTA形成肾肿瘤中起关键作用。
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 mu M) 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 (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 occurrence of cytogenetic abnormalities and may therefore play a critical role in renal tumor formation by OTA.