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 these fibers involved in cancer development have not been elucidated yet. Previous works show that chrysotile fibers induce features of cancer cells, such as aneuploidy, multinucleation and multipolar mitosis. In the present study, normal and cancer derived human cell lines were treated with chrysotile and the cellular and molecular mechanisms related to generation of aneuploid cells was elucidated. The first alteration observed was cytokinesis regression, the main cause of multinucleated cells formation and centrosome amplification. The multinucleated cells formed after cytokinesis regression were able to progress through cell cycle and generated aneuploid cells after abnormal mitosis. To understand the process of cytokinesis regression, localization of cytokinetic proteins was investigated. It was observed mislocalization of Anillin, Aurora B, Septin 9 and Alix in the intercellular bridge, and no determination of secondary constriction and abscission sites. Fiber treatment also led to overexpression of genes related to cancer, cytokinesis and cell cycle. The results show that chrysotile fibers induce cellular and molecular alterations in normal and tumor cells that have been related to cancer initiation and progression, and that tetraploidization and aneuploid cell formation are striking events after fiber internalization, which could generate a favorable context to cancer development.

Structure and function of Septin 9 and its role in human malignant tumors

“…High SEPT9 expression promotes genetic instability, causes mitotic spindle defects, hinders the cytoplasmic division, and leads to chromosomal segregation disorders. If SEPT9 gene expression is downregulated or absent in actively mitotic cells, cell division is impaired and cannot be completed and the spindle cannot be correctly attached, resulting in polyploidy and aneuploidy[ 40 - 42 ].…”

“…Thus, phosphorylated SEPT9 regulates mitosis and promotes cell proliferation and survival[ 48 ]. SEPT9 mislocalization can mediate cytokinesis failure and lead to aneuploidy, centrosome amplification, and multipolar mitoses[ 40 ]. Elongated N-terminal tail of SEPT9 is enriched with proline residues, and interacts with actin microfilaments and microtubule[ 31 ].…”

Evaluating the mechanistic evidence and key data gaps in assessing the potential carcinogenicity of carbon nanotubes and nanofibers in humans

“…Increased centromere positive micronuclei suggest that CNF is also an aneugen (Kisin et al 2011). Aneuploidy is an early event in the progression of many types of cancers (Pitot & Dragan 1993; Yegles et al 1995; Sargent et al 1996; Duesberg et al 2011; Cortez et al 2016). …”

Cancer-Related Functions and Subcellular Localizations of Septins

“…There, the septin ring facilitates the recruitment of Chmp4B, allowing the assembly of the ESCRT III complex, which actually mediates the abcission step (Renshaw et al, 2014). A recent study on the effects of chrysotile fibers (responsible of mesothelioma, lung cancer, and asbestos) points out the role of cytokinesis failure mediated by an overexpression of SEPT2 and by anillin and SEPT9 mislocalizations, in causing aneuploidy, centrosome amplification, and multipolar mitoses (Cortez et al, 2016), which are frequent in cancer cells.…”