title: RNA interference targeting survivin exerts antitumoral effects in vitro and in established glioma xenografts in vivo.
abstract: Malignant glioma represents the most common primary adult brain tumor in Western industrialized countries. Despite aggressive treatment modalities, the median survival duration for patients with glioblastoma multiforme (GBM), the highest grade malignant glioma, has not improved significantly over past decades. One promising approach to deal with GBM is the inactivation of proteins essential for survival or progression of glioma cells by means of RNA interference (RNAi) techniques. A likely candidate for an RNAi therapy of gliomas is the inhibitor of apoptosis protein survivin. Survivin is involved in 2 main cellular processes-cell division and inhibition of apoptosis. We show here that stable RNAi of survivin induced polyploidy, apoptosis, and impaired proliferation of human U343-MG, U373-MG, H4, and U87-MG cells and of primary glioblastoma cells. Proteome profiler arrays using U373-MG cells identified a novel set of differentially expressed genes upon RNAi-mediated survivin knockdown. In particular, the death receptor TRAIL R2/DR5 was strongly upregulated in survivin-depleted glioma cells, inducing an enhanced cytotoxic response of allogeneic human NK cells. Moreover, an experimental in vivo therapy using polyethylenimine (PEI)/siRNA complexes for survivin knockdown efficiently blocked tumor growth of established subcutaneous U373-MG tumors and enhanced survival of NMRI(nu/nu) mice orthopically transplanted with U87-MG cells. We conclude that survivin is functionally relevant in gliomas and that PEI-mediated exogenous delivery of siRNA targeting survivin is a promising strategy for glioblastoma therapy.
authors.affiliation: Department of Neurosurgery, University Hospital Carl Gustav Carus, Dresden, Germany.
authors.forename: Sandy
authors.initials: S
authors.lastname: Hendruschk
authors.forename: Ralf
authors.initials: R
authors.lastname: Wiedemuth
authors.forename: Achim
authors.initials: A
authors.lastname: Aigner
authors.forename: Katrin
authors.initials: K
authors.lastname: Töpfer
authors.forename: Marc
authors.initials: M
authors.lastname: Cartellieri
authors.forename: Daniel
authors.initials: D
authors.lastname: Martin
authors.forename: Matthias
authors.initials: M
authors.lastname: Kirsch
authors.forename: Chrysanthy
authors.initials: C
authors.lastname: Ikonomidou
authors.forename: Gabriele
authors.initials: G
authors.lastname: Schackert
authors.forename: Achim
authors.initials: A
authors.lastname: Temme
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D002469:Cell Separation; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015316:Genetic Therapy / Q000379:methods*; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D020287:In Situ Nick-End Labeling; D051034:Inhibitor of Apoptosis Proteins / Q000235:genetics*; D051379:Mice; D040081:Protein Array Analysis; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000494:pharmacology*; D060888:Real-Time Polymerase Chain Reaction; D000077022:Survivin; D014161:Transduction, Genetic; D023041:Xenograft Model Antitumor Assays
chemical_list: C107489:BIRC5 protein, human; D051034:Inhibitor of Apoptosis Proteins; D034741:RNA, Small Interfering; D000077022:Survivin