Department of Urology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
Comput Math Methods Med. 2022 Jun 20;2022:4182401. doi: 10.1155/2022/4182401. eCollection 2022.
Prostate cancer (PCa) is the most frequent cancer in men. Developing new treatment methods for CRPC will be a significant challenge in the clinical treatment of PCa. In conclusion, the results of this study show that NRF2 is downregulated in untreated PCa samples compared to normal PCa samples; however, it was upregulated in mCRPC samples compared to HSPC samples. These results demonstrated that NRF2 may serve as a tumor suppressor in tumorigenesis but promote PCa androgen-independent transferring after ADT treatment. Bioinformatics analysis showed that NRF2 was related to multiple signaling, such as the AGE-RAGE pathway, MAPK pathway, NF-kappa B signaling, PI3K-Akt signaling pathway, and VEGF signaling pathway. Moreover, we revealed that the NRF2 inhibitor significantly inhibited tumorigenicity of CRPC cells in vitro. Of note, combination of the NRF2 inhibitor and autophagy inhibitor had a more significantly suppressive role than either ML385 or CQ, indicating that combination of CQ (autophagy inhibitor) and ML385 (NRF2 inhibitor) is a potential treatment of CRPC. Finally, we conformed that high levels of autophagy regulators LC3B, ULK1, and beclin1 significantly correlated to longer PSA recurrence-free survival time. We think that this study could provide more evidence to confirm that NRF2 is a crucial regulator and targeting NRF2 and autophagy is a potential therapy option for CRPC.
前列腺癌（PCa）是男性最常见的癌症。开发新的 CRPC 治疗方法将是 PCa 临床治疗的重大挑战。总之，本研究结果表明，与正常 PCa 样本相比，未经治疗的 PCa 样本中 NRF2 下调；然而，与 HSPC 样本相比，mCRPC 样本中 NRF2 上调。这些结果表明，NRF2 可能在肿瘤发生中作为肿瘤抑制因子，但在 ADT 治疗后促进 PCa 雄激素非依赖性转移。生物信息学分析表明，NRF2 与多种信号通路有关，如 AGE-RAGE 通路、MAPK 通路、NF-κB 信号通路、PI3K-Akt 信号通路和 VEGF 信号通路。此外，我们揭示了 NRF2 抑制剂在体外显著抑制 CRPC 细胞的致瘤性。值得注意的是，NRF2 抑制剂和自噬抑制剂的联合作用比 ML385 或 CQ 更显著，表明 CQ（自噬抑制剂）和 ML385（NRF2 抑制剂）的联合使用是 CRPC 的一种潜在治疗方法。最后，我们证实高水平的自噬调节剂 LC3B、ULK1 和 beclin1 与更长的 PSA 无复发生存时间显著相关。我们认为本研究可以提供更多证据证实 NRF2 是一个关键的调节因子，靶向 NRF2 和自噬是 CRPC 的一种潜在治疗选择。
