Abstract
BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with limited treatment options and poor prognosis. Identifying novel molecular regulators is essential for improving therapeutic strategies. In this study, we identified Sortilin-related VPS10 domain-containing receptor 3 (SorCS3) as a novel tumor suppressor candidate in ACC. METHODS: Through expression detection and functional validation, we investigated the role of SorCS3, a member of the VPS10p-domain receptor family, in ACC. Expression data from TCGA and clinical tissue samples were analyzed. Endocytic activity, protein interactions, and downstream signaling were examined using immunofluorescence, co-immunoprecipitation (Co-IP), and western blotting in ACC cell lines. RESULTS: SorCS3, previously regarded as CNS-specific, was detected in ACC tissues and cell lines. Low SorCS3 expression was associated with reduced overall survival (OS) and disease-specific survival (DSS). Functional assays showed that SorCS3 enhanced endocytosis and colocalized with early endosomes. Co-IP revealed a physical or indirect interaction between SorCS3 and Insulin-like growth factor 2 receptor (IGF2R), a multifunctional receptor involved in IGF-II degradation and signal attenuation. SorCS3 overexpression (OE-SorCS3) increased IGF2R protein levels and suppressed PI3K/Akt and MAPK/Erk signaling. Blocking endocytosis partially reversed these effects, supporting a receptor trafficking-dependent mechanism. CONCLUSIONS: In this study, we identified SorCS3 as a novel tumor suppressor candidate in ACC. Although previously thought to be CNS specific, SorCS3 was found to be expressed in ACC tissues and cell lines. Low SorCS3 levels correlated with poor patient survival in the TCGA cohort. Functionally, SorCS3 enhanced endocytosis in ACC cells and physically or indirectly interacted with IGF2R. OE-SorCS3 increased IGF2R protein levels and reduced phosphorylation of Akt/Erk, suggesting tumor-suppressive effects through IGF2R stabilization and signaling inhibition. Overall, our findings highlight the SorCS3-IGF2R axis as a previously unrecognized regulatory mechanism in ACC progression and suggest that receptor trafficking could be a viable therapeutic target in this malignancy.