Abstract
While androgen deprivation therapy (ADT) continues to be a fundamental aspect of prostate cancer treatment, the development of castration-resistant prostate cancer (CRPC) emphasizes the necessity for a more profound understanding of the tumor microenvironment (TME). Normal fibroblasts (NFs) and cancer-associated fibroblasts (CAFs) were isolated and characterized from normal control and prostate cancer specimens, respectively. PC3 and DU145 cells, and the corresponding enzalutamide resistant counterparts, PC3-EnzR and DU145-EnzR, were co-cultured with NFs or CAFs to evaluate the effects of TME in driving enzalutamide resistance. Cell viability of prostate cancer cells was examined by MTT assay. The study also utilized recombinant human neuregulin-1 (NRG1) protein and siRNA to modulate NRG1 expression in CAFs. RT-qPCR, Western blot, and ELISA were employed to assess gene and protein expressions related to the NRG1-HER3 signaling pathway and its association with enzalutamide resistance. CAFs significantly promoted cell growth and enzalutamide resistance of PC3-EnzR and DU145-EnzR cells through substantial increased secretion of NRG1 by CAFs. Co-culturing enzalutamide-resistant prostate cancer cells (PC3-EnzR and DU145-EnzR) with CAFs further enhanced enzalutamide resistance, as evidenced by elevated IC50 values. Inhibition of NRG1 in CAFs attenuated their impact on enzalutamide resistance, providing insight into the role of NRG1 in mediating the crosstalk between CAFs and prostate cancer in the context of enzalutamide resistance. This study elucidates the pivotal role of CAF-secreted NRG1 in promoting enzalutamide resistance in prostate cancer, providing valuable insights for developing targeted therapeutic strategies to overcome resistance in advanced prostate cancer.