gms | German Medical Science

Objective: Survivin (gene BIRC5) belongs to the inhibitor of apoptosis proteins (IAPs). It has been hypothesized that Survivin's IAP function promotes tumor progression and confers resistance against standard therapies. Another function of Survivin is restricted to mitosis, where Survivin is an indispensible part of the chromosomal passenger complex (CPC) which regulates proper chromatid segregation and cytokinesis. So far, the influence of overexpressed Survivin levels on chromosome instability and progression of gliomas has not been addressed. The aim of this study was to investigate a possible role of the CPC function of Survivin in induction of chromosomal instability, eventually driving tumor progression and development of resistant glioma cell populations.

Method: U373-MG cells were transduced either with lentiviral vectors encoding Survivin-myc-HA or empty vectors. Proliferation, basal apoptosis and ceramide C2 (CC2)-induced intrinsic apoptosis was measured by BrdU incorporation assays and AnnexinV/PI-staining. The development of temozolomide (TMZ) resistance of transduced U373-MG cells was assessed by clonogenic survival assays. For in vivo experiments tumor cells were additionally transduced with mycn or respective empty vector and subcutaneously injected into NMRInu/nu mice.

Results: The overexpression of Survivin had no effect on the clonal survival of U373-MG cells. However, under TMZ treatment, cells overexpressing Survivin showed a significantly better survival rate than the mock-transduced cells. In order to elucidate whether this effect was mediated by the IAP or the CPC function of Survivin, we treated the cells with CC2 and TMZ and analyzed them by Annexin V staining. Interestingly, apoptosis was significantly increased in cells that overexpressed Survivin when compared to controls. Besides this, transduction with Survivin resulted in the appearance of polyploid cell populations, indicative of defective mitosis.

Finally, concomitant overexpression of mycn+Survivin gave rise to tumors with a shortened latency and shortened tumor doubling time compared to tumors formed by mycn-transduced cells.

Conclusions: Our results indicate that deregulated Survivin expression levels in glioma cells contribute to TMZ resistance, enhance tumor growth and increase malignancy. In conjunction with the appearance of mitotic defects in Survivin-transduced cells it might be concluded that a deregulated "CPC" function of Survivin drives tumor progression and might cause TMZ-resistance through adaptive evolution.