Abstract
Despite their ubiquitous expression and high conservation during evolution, precise cellular functions of vault ribonucleoparticles, mainly built of multiple major vault protein (MVP) copies, are still enigmatic. With regard to cancer, vaults were shown to be upregulated during drug resistance development as well as malignant transformation and progression. Such in a previous study we demonstrated that human astrocytic brain tumours including glioblastoma are generally high in vault levels while MVP expression in normal brain is comparably low. However a direct contribution to the malignant phenotype in general and that of glioblastoma in particular has not been established so far. Thus we address the questions whether MVP itself has a pro-tumorigenic function in glioblastoma. Based on a large tissue collection, we re-confirm strong MVP expression in gliomas as compared to healthy brain. Further, the impact of MVP on human glioblastoma aggressiveness was analysed by using gene transfection, siRNA knock-down and dominant-negative genetic approaches. Our results demonstrate that MVP/vaults significantly support migratory and invasive competence as well as starvation resistance of glioma cells in vitro and in vivo. The enhanced aggressiveness was based on MVP-mediated stabilization of the epidermal growth factor receptor (EGFR)/phosphatidyl-inositol-3-kinase (PI3K) signalling axis. Consequently, MVP overexpression resulted in enhanced growth and brain invasion in human glioblastoma xenograft models. Our study demonstrates, for the first time, that vaults have a tumour-promoting potential by stabilizing EGFR/PI3K-mediated migration and survival pathways in human glioblastoma.
Highlights
Human glioblastoma multiforme (WHO grade IV, GBM) represents the most common and aggressive form of primary brain tumour in adults with a median survival of less than 15 months [1]
Selection for major vault protein (MVP)-positive clones was significantly more efficient as compared to the vector control already indicating a positive impact of MVP expression on H7 clonogenic cell survival (Figure 1C and D)
We demonstrate that MVP supports aggressiveness of human GBM cells and xenografts by fostering an epidermal growth factor receptor (EGFR)/PI3K/ AKT pathway-mediated migratory/invasive potential as well as starvation resistance
Summary
Human glioblastoma multiforme (WHO grade IV, GBM) represents the most common and aggressive form of primary brain tumour in adults with a median survival of less than 15 months [1]. This dismal prognosis is based on both, the resistance to current therapeutic options [2]. The successful chemotherapeutic treatment of brain tumours is mainly limited by the blood-brain-barrier and the expression of ABC-transporter proteins, acting as drug efflux pumps [4]. Another protein frequently linked with drug resistance is the major vault protein (MVP), www.impactjournals.com/oncotarget. The role of MVP and vaults in drug resistance is controversially discussed [5, 11, 12]
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