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Multipolar mitosis and aneuploidy after chrysotile treatment: a consequence of abscission failure and cytokinesis regression

Abstract

Chrysotile, like other types of asbestos, has been associated with mesothelioma,lung cancer and asbestosis. However, the cellular abnormalities induced by thesefibers involved in cancer development have not been elucidated yet. Previous worksshow that chrysotile fibers induce features of cancer cells, such as aneuploidy,multinucleation and multipolar mitosis. In the present study, normal and cancerderived human cell lines were treated with chrysotile and the cellular and molecularmechanisms related to generation of aneuploid cells was elucidated. The firstalteration observed was cytokinesis regression, the main cause of multinucleatedcells formation and centrosome amplification. The multinucleated cells formedafter cytokinesis regression were able to progress through cell cycle and generatedaneuploid cells after abnormal mitosis. To understand the process of cytokinesisregression, localization of cytokinetic proteins was investigated. It was observedmislocalization of Anillin, Aurora B, Septin 9 and Alix in the intercellular bridge, andno determination of secondary constriction and abscission sites. Fiber treatmentalso led to overexpression of genes related to cancer, cytokinesis and cell cycle.The results show that chrysotile fibers induce cellular and molecular alterations innormal and tumor cells that have been related to cancer initiation and progression,and that tetraploidization and aneuploid cell formation are striking events after fiberinternalization, which could generate a favorable context to cancer development. (AU)