Wang Chunyu, Cao Hongwen, Sun Peng, Chen Lei, Feng Yigeng, Gao Renjie
Surgical Department I (Urology Department), LONGHUA Hospital Shanghai University of Traditional Chinese Medicine No. 725 Wanping Road South, Xuhui District, Shanghai 200032, China.
Am J Cancer Res. 2024 Oct 15;14(10):4830-4840. doi: 10.62347/OTTR3398. eCollection 2024.
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.
虽然雄激素剥夺疗法（ADT）仍然是前列腺癌治疗的一个基本方面，但去势抵抗性前列腺癌（CRPC）的出现凸显了更深入了解肿瘤微环境（TME）的必要性。分别从正常对照和前列腺癌标本中分离并鉴定了正常成纤维细胞（NFs）和癌相关成纤维细胞（CAFs）。将PC3和DU145细胞以及相应的恩杂鲁胺耐药细胞PC3-EnzR和DU145-EnzR与NFs或CAFs共培养，以评估TME在驱动恩杂鲁胺耐药中的作用。通过MTT法检测前列腺癌细胞的细胞活力。该研究还利用重组人神经调节蛋白-1（NRG1）蛋白和小干扰RNA（siRNA）来调节CAFs中NRG1的表达。采用逆转录-定量聚合酶链反应（RT-qPCR）、蛋白质免疫印迹法（Western blot）和酶联免疫吸附测定（ELISA）来评估与NRG1-人表皮生长因子受体3（HER3）信号通路相关的基因和蛋白表达及其与恩杂鲁胺耐药的关系。CAFs通过大量增加NRG1的分泌，显著促进了PC3-EnzR和DU145-EnzR细胞的生长和恩杂鲁胺耐药性。将恩杂鲁胺耐药的前列腺癌细胞（PC3-EnzR和DU145-EnzR）与CAFs共培养进一步增强了恩杂鲁胺耐药性，IC50值升高证明了这一点。抑制CAFs中的NRG1可减弱其对恩杂鲁胺耐药性的影响，这为在恩杂鲁胺耐药背景下NRG1在介导CAFs与前列腺癌之间相互作用中的作用提供了见解。本研究阐明了CAF分泌的NRG1在促进前列腺癌恩杂鲁胺耐药中的关键作用，为开发靶向治疗策略以克服晚期前列腺癌的耐药性提供了有价值的见解。
