Major vault protein supports glioblastoma survival and migration by upregulating the EGFR/PI3K signalling axis.
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.
Institute of Cancer Research, Department of Medicine I.
Daniela
D
Lötsch
Elisabeth
E
Steiner
Klaus
K
Holzmann
Sabine
S
Spiegl-Kreinecker
Christine
C
Pirker
Juraj
J
Hlavaty
Helga
H
Petznek
Balazs
B
Hegedus
Tamas
T
Garay
Thomas
T
Mohr
Wolfgang
W
Sommergruber
Michael
M
Grusch
Walter
W
Berger
D000328:Adult; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D002470:Cell Survival; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D015854:Up-Regulation; D020394:Vault Ribonucleoprotein Particles / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D000099187:Major Vault Protein
D066246:ErbB Receptors; D019869:Phosphatidylinositol 3-Kinases; D020394:Vault Ribonucleoprotein Particles; D000099187:Major Vault Protein; C512478:EGFR protein, human