gms | German Medical Science

Objective: Survivin, a protein that belongs to the inhibitor of proteins (IAPs) family, is highly expressed in cancer cells but is almost absent in normal tissue. It was actually shown that Survivin is one of the four most highly expressed genes found in tumors. It is also widely accepted that Survivin plays an important and unique role in the regulation of mitotic events and that its main molecular function is linked to the control of the spindle assembly checkpoint and cytokinesis. The aim of this study was to elucidate the consequences on chromosome stability of the overexpression of Survivin in glioma cells.

Method: Glioma cell lines (U373-MG, U87-MG and U87shp53) were transduced with retroviral vectors encoding Survivin-myc-HA. As controls, cells transduced with an empty vector (mock) were used. 72 hours after transduction, cells were subjected to flow cytometry, apoptosis assays, polyploidy analysis, DNA damage analysis, Western Blot analysis and confocal microscopy.

Results: The exogenous overexpression of Survivin caused a significant increase in the fraction of polyploid U373-MG cells and U87shp53 cells when compared to mock-transduced controls. However, there was no increase observed in the fraction of polyploid cells in U87-MG wild type cells with ectopic overexpression of Survivin-myc-HA. Western blotting and confocal laser scanning analysis showed that cells overexpressing Survivin suffered from DNA damage (as revealed by using the DNA damage marker γH2AX). Furthermore, defective mitosis led to extra and lagging chromosomes, chromosome misalignment and chromosomal bridges.

Conclusions: Our results suggest that deregulated Survivin expression levels might contribute to chromosomal instability and to tumor progression. An understanding of the biological mechanisms that account for aneuploidy could lead to useful insights with respect to novel anti-cancer therapeutic approaches in glioma.