siRNA targeting Notch-1 decreases glioma stem cell proliferation and tumor growth

Abstract

Glioblastoma multiforme (GBM), the most common brain tumor in adults, is neurologically destructive and has a dismal response to virtually all therapeutic modalities. One phenomenon that can contribute to this complexity is the presence of a relatively small subset of glioma stem cells (GSCs) within the tumor and the activation of pathways that control cellular differentiation. The Notch signaling pathway, which is responsible for maintaining a balance between cell proliferation and apoptosis, is believed to be deregulated in cancer stem cells (CSCs), leading to tumor growth through the generation or expansion of CSCs. In this study, Notch-1 small interfering RNA (siRNA) was used to silence Notch-1 gene expression in GSCs. An MTT assay demonstrated inhibitory effects on the proliferation of GSCs in vitro. Real-time PCR showed that Notch-1 expression levels were markedly decreased in GSCs transfected with Notch-1 siRNA in vitro. Notch-1 silenced GSCs engrafted on Balb/c nude mice showed a significantly greater reduction in oncogenicity than the control group (P < 0.05). Furthermore, direct intratumoral injections of Notch-1-siRNA/PEI significantly delayed the growth of pre-established tumors in nude mice (P < 0.05). These results suggest that siRNA-mediated silencing of the Notch-1 gene may represent a novel target for gene therapy of GBM.