ABSTRACT Background Megalin (LRP2) is a multifunctional endocytic receptor whose role in prostate cancer (PCa), particularly in cancer stem cells (CSCs) and metastatic progression, remains largely unexplored. Methods We analyzed LRP2 mRNA and protein expression in DU‐145, PC‐3, and RWPE1 cells and their CD133 high /CD44 high CSCs via qRT‐PCR and immunofluorescence, in both 2D and 3D cultures. Public RNA‐seq data (TCGA, WCDT‐MCRPC) were used to assess LRP2, CD133, and CD44 across normal, primary, and metastatic tumors. Gene Set Enrichment Analysis (GSEA) and correlation with AR, VDR, and stemness genes were performed. Result LRP2 was significantly upregulated in DU‐145 cells and CSCs in the 3D culture system. In contrast, PC‐3 CSCs showed reduced LRP2 expression. In clinical datasets, LRP2 was highest in metastatic tumors (log2FC = 3.58), with bone (M1B) and other parts of the body (M1C) subtypes exhibiting elevated levels compared to primary tumors. CD133 was consistently downregulated in metastases. GSEA highlighted LRP2 involvement in lipid, retinoid, and steroid metabolism. LRP2 correlated positively with VDR and negatively with AR in M1C tumors. Conclusion LRP2 shows subtype‐specific expression patterns in PCa, with elevated levels in DU‐145 CSCs and metastatic tumors. Its link to metabolic pathways and inverse relationship with AR suggest a potential role in therapy resistance and metastasis.
Mukhtarova et al. (2025) studied this question.