Zhoushi Qiling decoction inhibits neuregulin 1 secreted from cancer-associated fibroblasts to ameliorate enzalutamide resistance in prostate cancer.

BACKGROUND AND AIM: Zhoushi Qiling decoction (ZQD) has emerged as a promising therapeutic agent for improving outcomes in prostate cancer treatment. This study aimed to evaluate the efficacy of ZQD on enzalutamide-resistant prostate cancer cells and to elucidates the underlying mechanisms.

EXPERIMENTAL PROCEDURE: A co-culture model consisting of cancer-associated fibroblasts (CAFs) and enzalutamide-resistant prostate cancer cells was established and treated with ZQD-containing serum. Cell proliferation and viability were assessed using colony formation and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays. The anti-tumor effects of ZQD were further evaluated in an in vivo xenograft model using enzalutamide-resistant PC3-EnzR cells treated with ZQD for 28 days. Expression of relevant biomarkers in cell lines and tumor tissues was analyzed by qRT-PCR and Western blotting.

RESULTS

ZQD-containing serum inhibited the expression of neuregulin 1 (NRG1) in CAFs. It also reversed CAF-induced enzalutamide resistance and reduced CAF-stimulated proliferation of enzalutamide-resistant prostate cancer cells. In addition, ZQD suppressed NRG1 secretion and phosphorylation of human epidermal growth factor receptor 3 (HER3) in these cells. The serum also demonstrated inhibitory effects on matrix metalloproteinases (MMP-1 and MMP-9) in enzalutamide-resistant prostate cancer cells. In vivo, ZQD significantly suppressed tumor growth and reduced NRG1 expression.

CONCLUSION

ZQD effectively inhibits NRG1 secretion from CAFs and mitigates enzalutamide resistance in prostate cancer. These findings provide a scientific basis for the potential clinical application of ZQD in overcoming enzalutamide resistance in prostate cancer treatment.