Article
RNA interference targeting Survivin exerts anti-tumoral effects in vitro and in glioma xenografts
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Published: | September 16, 2010 |
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Objective: Despite multimodal treatments, the median survival of patients suffering from glioblastoma (GB) has not improved over the past decades. One promising approach to deal with GB is the inactivation of proteins essential for survival or progression by means of RNA interference (RNAi) techniques. A candidate for an RNAi therapy of gliomas is the inhibitor of apoptosis protein (IAP) survivin. Survivin is involved in two main cellular processes, cell division and inhibition of apoptosis. Since loss of survivin results in mitotic defects and cannot be compensated by other IAP familiy members such as XIAP or cIAP we sought to establish a survivin-RNAi-therapy of gliomas.
Methods: Knock down of survivin expression in glioma cells and xenografts was accomplished by retroviral shRNA vectors and polyethlyenimine-(PEI) complexed siRNA molecules, respectively. RNAi-effects were investigated by standard proliferation assays, measurement of tumor growth, QRT-PCR, and protein analyses, including proteome profiler blots.
Results: RNAi of survivin induced polyploidy and impaired proliferation of glioma cells. An upregulation of TRAIL and CD95/Fas was observed, making the glioma cells susceptible to NK cells. In vivo experiments using PEI-siRNA targeting survivin efficiently blocked subcutaneous U373 xenograft growth.
Conclusions: Survivin-RNAi is a promising strategy to impair glioma growth. Further experiments using immune-competent syngeneic mice are warranted to confirm the potential of this therapeutic approach.