PDGFC facilitates enzalutamide resistance in prostate cancer through autocrine activation of the RAP1-MAPK pathway

Prostate cancer (PCa) is a highly heterogeneous malignant tumor within the male genitourinary system, characterized by its invasive and metastatic potential. Although the second-generation androgen receptor (AR) antagonist enzalutamide has shown therapeutic efficacy in PCa patients, enzalutamide resistance (EnzaR) will be inevitably develops and the underlying mechanisms are not fully understood. In this study, we confirmed that the expression of Platelet-Derived Growth Factor C (PDGFC) elevated in EnzaR PCa and promoted the proliferation of PCa in vitro and in vivo. Silencing PDGFC in EnzaR cells notably enhances the sensitivity of EnzaR PCa cells to enzalutamide, thereby inhibiting the progressive of PCa. Mechanistically, overexpressed PDGFC activates the PDGFR-RAP1-MAPK signaling cascade in an autocrine fashion within EnzaR cells. PDGFR inhibitors alone or combined with enzalutamide significantly suppressed the progression of EnzaR PCa xenografts. Additionally, we demonstrated that the transcription factor STAT4 binds to a specific DNA sequence in the PDGFC promoter region, which is essential for PDGFC upregulation. Collectively, our results confirmed the pivotal role of PDGFC in PCa cells developing resistant to enzalutamide therapy, suggesting that targeting PDGFC may serve as a promising therapeutic strategy for EnzaR PCa.