Extracellular Thimet Oligopeptidase is Released with Extracellular Vesicles from Human Prostate Cancer Cells

Abstract

ABSTRACTAndrogen signaling plays a central role in the development of prostate cancer. Androgen hormone synthesis is tightly governed by the hypothalamic–pituitary–gonadal (HPG) axis, including gonadotropin-releasing hormone (GnRH). Thimet oligopeptidase (TOP) is a biologically significant peptidase known to cleave GnRH and potentially regulate its activity. Thus, TOP can play an important role in the HPG axis through regulating the downstream production and release of gonadal steroid hormones, including androgens, which may further affect prostate cancer development. TOP is known to be secreted out to the extracellular space. Here, we report that extracellular TOP can be associated with extracellular vesicles (EVs). Western blot analysis of EVs isolated from PC3 or DU145 prostate cancer cells revealed that TOP protein is, indeed, carried by the EVs. Budding of EVs from stimulated PC3 prostate cancer cells can also be visualized by confocal microscopy. Significantly, the TOP enzyme carried by EVs is enzymatically active. The present study shows that EV-associated TOP is a novel form of this extracellular peptidase that may play a role in the disease progression of prostate cancer cells.