SVIP reduces IGFBP-2 expression and inhibits glioblastoma progression via stabilizing PTEN.

ABSTRACT

Glioblastoma (GBM) presents significant challenges due to its invasive nature and genetic heterogeneity. In this study, we investigated the impact of Small VCP/P97-Interacting Protein (SVIP) on GBM progression. Our results revealed elevated expression of Insulin-like Growth Factor Binding Protein 2 (IGFBP-2) and STIP1 homology and U-box containing protein 1 (STUB1), coupled with reduced SVIP levels in GBM samples. Notably, high IGFBP-2 expression correlated with poor prognosis. Mechanistically, SVIP competitively inhibited STUB1, selectively binding to VCP/p97, thereby reducing PTEN degradation. This SVIP-mediated regulation exerted influence on the PTEN/PI3K/AKT/mTOR pathway, leading to the suppression of GBM progression. Co-localization experiments demonstrated that SVIP hindered PTEN ubiquitination and degradation by outcompeting STUB1 for VCP/p97 binding. Moreover, SVIP overexpression resulted in reduced activation of AKT/mTOR signaling and facilitated autophagy. In vivo experiments using a GBM xenograft model substantiated the tumor-suppressive effects of SVIP, evident by suppressed tumor growth, decreased IGFBP-2 expression, and improved survival rates. Collectively, our findings underscore the functional significance of SVIP in GBM progression. By inhibiting STUB1 and stabilizing PTEN, SVIP modulates the expression of IGFBP-2 and attenuates the activation of the PI3K/AKT/mTOR pathway, thereby emerging as a promising therapeutic target for GBM treatment.