Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, 430071, P. R. China.
Huaihe Hospital of Henan University, Kaifeng, 475000, P. R. China.
J Transl Med. 2024 Jun 6;22(1):538. doi: 10.1186/s12967-024-05335-z.
Apalutamide, a novel endocrine therapy agent, has been shown to significantly improve the prognosis of patients with metastatic hormone-sensitive prostate cancer (mHSPC). However, resistance to apalutamide has also been reported, and the underlying mechanism for this response has yet to be clearly elucidated. First, this study established apalutamide-resistant prostate cancer (PCa) cells, and confirmed that apalutamide activated the release of calcium ions (Ca) and endoplasmic reticulum stress (ERS) to enhance autophagy. Second, RNA sequencing, western blotting, and immunohistochemistry revealed significantly decreased Calpain 2 (CAPN2) expression in the apalutamide-resistant PCa cells and tissues. Furthermore, immunofluorescence and transmission electron microscopy (TEM) showed that CAPN2 promoted apalutamide resistance by activating protective autophagy. CAPN2 promoted autophagy by reducing Forkhead Box O1 (FOXO1) degradation while increasing nuclear translocation via nucleoplasmic protein isolation and immunofluorescence. In addition, FOXO1 promoted protective autophagy through the transcriptional regulation of autophagy-related gene 5 (ATG5). Furthermore, a dual-fluorescence assay confirmed that transcription factor 3 (ATF3) stimulation promoted CAPN2-mediated autophagy activation via transcriptional regulation. In summary, CAPN2 activated protective autophagy by inhibiting FOXO1 degradation and promoting its nuclear translocation via transcriptional ATG5 regulation. ATF3 activation and transcriptional CAPN2 regulation jointly promoted this bioeffect. Thus, our findings have not only revealed the mechanism underlying apalutamide resistance, but also provided a promising new target for the treatment of metastatic PCa.
阿帕鲁胺是一种新型的内分泌治疗药物，已被证明能显著改善转移性激素敏感前列腺癌（mHSPC）患者的预后。然而，也有报道称阿帕鲁胺存在耐药性，其耐药机制尚未明确。首先，本研究建立了阿帕鲁胺耐药前列腺癌（PCa）细胞系，并证实阿帕鲁胺通过激活钙离子（Ca）释放和内质网应激（ERS）来增强自噬。其次，RNA 测序、western blot 和免疫组化显示，阿帕鲁胺耐药 PCa 细胞和组织中钙蛋白酶 2（CAPN2）表达显著降低。此外，免疫荧光和透射电子显微镜（TEM）显示，CAPN2 通过激活保护性自噬来促进阿帕鲁胺耐药。CAPN2 通过减少叉头框蛋白 O1（FOXO1）降解并通过核质蛋白分离和免疫荧光增加核易位来促进自噬。此外，FOXO1 通过转录调控自噬相关基因 5（ATG5）促进保护性自噬。此外，双荧光测定法证实转录因子 3（ATF3）刺激通过转录调控 CAPN2 介导的自噬激活。总之，CAPN2 通过抑制 FOXO1 降解并通过转录调控 ATG5 促进其核易位来激活保护性自噬。ATF3 激活和 CAPN2 转录调控共同促进了这种生物效应。因此，我们的研究结果不仅揭示了阿帕鲁胺耐药的机制，还为转移性 PCa 的治疗提供了一个有前途的新靶点。
