PDGFC facilitates enzalutamide resistance in prostate cancer through activation of the Rap1-MAPK pathway.

Purpose: 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 inevitably develop and the underlying mechanisms are not fully understood.

Methods: Platelet Derived Growth Factor C (PDGFC) expression in PCa cells was measured by qRT‒PCR and Western blot. The effect of PDGFC on PCa was examined both in vitro and in vivo. CCK8, Colony formation, and EdU assays were used to assess the phenotypes of PCa cells. A tumor xenograft model was used to evaluate the impact of PDGFC on PCa in vivo. Luciferase assays and chromatin immunoprecipitation (ChIP) assays were performed to demonstrate the mechanism of signal transducer and activator of transcription 4 (STAT4)-mediated transcriptional regulation of PDGFC.

Results: The expression of PDGFC is significant elevated in EnzaR PCa and positively correlates with PCa proliferation in vitro and in vivo. Silencing PDGFC increases the sensitivity of EnzaR PCa cells to enzalutamide, thereby inhibiting PCa progression. Mechanistically, overexpression of PDGFC activates the PDGFR-Rap1-MAPK signaling in an autocrine manner in EnzaR cells. Notably, PDGFR inhibitors, alone or combined with enzalutamide, significantly inhibit xenograft progression in EnzaR PCa models. Additionally, the transcription factor STAT4 binds to a specific DNA sequence in the PDGFC promoter region, which is essential for PDGFC upregulation.

Conclusion: Our results confirmed the pivotal role of PDGFC in the development of enzalutamide resistance in PCa. Targeting PDGFC or PDGFC mediate Rap1-MAPK pathway may serve as a promising therapeutic strategy for EnzaR PCa.