Proteomic Profiling reveals that DPP4 overexpression increases Cell Adhesion, inhibits cell migration, And Restores Androgen Sensitivity in Prostate Cancer

Dipeptidyl peptidase-4 (DPP4), a serine protease with both enzymatic and non-enzymatic roles, has emerged as a context-dependent modulator of tumor progression. In this study, we investigated the expression and function of DPP4 in androgen-sensitive and androgen-resistant prostate cancer (CRPC) models. Proteomic analysis of androgen-resistant prostate cells overexpressing DPP4, identified the involvement of the cellular adhesion molecules pathway. In prostate cells, lentiviral-mediated DPP4 overexpression restored androgen receptor (AR) signaling, inhibited epithelial-to-mesenchymal transition (EMT), and reduced cell migration, whereas DPP4 silencing produced the opposite effects. We demonstrate that DPP4 expression is downregulated in CRPC cells, and that treatment with capsaicin, a bioactive compound derived from red peppers, restores DPP4 expression. Moreover, DPP4 restoration by capsaicin suppresses prostate tumorigenesis in the TRAMP mice in vivo model of prostate cancer. Our results suggest that DPP4 could be a new target for castration resistant prostate cancer.