Exploring STEAP1 Expression in Prostate Cancer Cells in Response to Androgen Deprivation and in Small Extracellular Vesicles

Abstract The six-transmembrane epithelial antigen of the prostate (STEAP; STEAP1 and STEAP2) metalloreductases are therapeutic targets for advanced prostate cancer, and their expression has been linked to androgen receptor (AR) signaling; however, the regulatory mechanism and functions of STEAP1 and STEAP2 in prostate cancer progression remain elusive. In this study, we explore how in vitro androgen modulation and AR inhibition influence the expression of STEAP family members in cell lines with varying reliance on androgen signaling. Our data show that in response to androgen deprivation, STEAP1 and STEAP2 exhibit elevated transcript levels, whereas STEAP4 levels are reduced, mirroring the expression profile of kallikrein-related peptidase 3 (KLK3). As STEAP1 and STEAP2 are implicated in the exocytic pathway, we evaluated expression profiles in small extracellular vesicles (sEV) released from prostate cancer cells and in circulating sEVs. STEAP1, but not STEAP2, is upregulated in sEVs from AR-negative cells, which express low cellular STEAP1, and AR-positive cells, which express high cellular STEAP1. These results indicate selective packaging of STEAP1 in prostate cancer cell–derived sEVs, irrespective of AR status and cellular STEAP1 expression levels. Finally, ex vivo analysis of circulating sEVs from genetically engineered mice carrying prostate cancer shows that STEAP1 is found in the sEV cargo and that its levels are independent of protumorigenic β1 integrin expression in the prostatic epithelium. Implications: Understanding how androgen dependence affects STEAP1 expression in both tumor cells and sEVs across distinct disease stages will illuminate the clinical benefit of combinatorial AR and STEAP1-directed therapies and inform the optimal placement of STEAP1 targeting within the prostate cancer disease continuum.