The Membrane Protein Sortilin Is a Potential Biomarker and Target for Glioblastoma

Abstract

Glioblastoma (GBM) is a devastating brain cancer with no effective treatment, and there is an urgent need for developing innovative biomarkers as well as therapeutic targets for better management of the disease. The membrane protein sortilin has recently been shown to participate in tumor cell invasiveness in several cancers, but its involvement and clinical relevance in GBM is unclear. In the present study, we explored the expression of sortilin and its potential as a clinical biomarker and therapeutic target for GBM. Sortilin expression was investigated by immunohistochemistry and digital quantification in a series of 71 clinical cases of invasive GBM vs. 20 non-invasive gliomas. Sortilin was overexpressed in GBM and, importantly, higher expression levels were associated with worse patient survival, pointing to sortilin tissue expression as a potential prognostic biomarker for GBM. Sortilin was also detectable in the plasma of GBM patients by enzyme-linked immunosorbent assay (ELISA), but no differences were observed between sortilin levels in the blood of GBM vs. glioma patients. In vitro, sortilin was detected in 11 brain-cancer-patient-derived cell lines at the anticipated molecular weight of 100 kDa. Interestingly, targeting sortilin with the orally bioavailable small molecule inhibitor AF38469 resulted in decreased GBM invasiveness, but cancer cell proliferation was not affected, showing that sortilin is targetable in GBM. Together, these data suggest the clinical relevance for sortilin in GBM and support further investigation of GBM as a clinical biomarker and therapeutic target.

Toxoplasma sortilin interacts with secretory proteins and it is critical for parasite proliferation

“…We further confirmed that sortilin is a promising drug target against T. gondii . Recent studies have shown that the sortilin inhibitor AF38469 effectively inhibits the invasion of pancreatic and brain cancers [ 31 , 32 ]. In the present study, AF38469 was found to inhibit T. gondii invasion and intracellular replication.…”

“…Molecular interaction experiments using bio-layer interferometry (BLI) technology confirmed that the Vps10, sortilin-C, and sortilin-M subdomains of sortilin were the binding regions of the transported proteins. The sortilin inhibitor AF38469, originally found to reduce the invasiveness of pancreatic cancer cells and glioblastoma cells [ 31 , 32 ], can also inhibit T. gondii cell invasion, replication in vitro, and infectivity in mice.…”

Enhancing Angioinvasion Assessment in Papillary Thyroid Cancer Via a Biomarker Panel Involving TAC, 8-OHdG, and Sortilin

“…To the best of our knowledge, there have been no prior studies investigating the serum profiling of sortilin in patients with PTC. However, both sortilin and 8-OHdG measurements have been associated with more aggressive breast cancer ( 22 , 23 ), pancreatic cancer ( 24 , 25 ), liver cancer ( 26 , 27 ), and glioblastoma ( 28 , 29 ).…”

The Role of Progranulin (PGRN) in the Pathogenesis of Glioblastoma Multiforme

“…The analysis of the properties of PGRN-related receptors and signalling pathways also poses promising research directions for further implementation in the therapy of brain tumours. The available data indicated that SORT1 is also highly upregulated within the cytoplasm and nuclei of gliomas obtained intraoperatively, where its expression level is positively correlated with the tumour grade [105,106]. Further studies also showed that SORT1 expression indicated a significantly poor prognosis, where 2-year survival rates for patients with high expression and low expression levels of SORT1 were 27% and 76%, and the 5-year survival rates of these patients were estimated to be 13% and 51%, respectively [107].…”