Recent studies have demonstrated the association of APP and Aβ with cancer, suggesting that BACE1 may play an important role in carcinogenesis. In the present study, we assessed BACE1’s usefulness as a therapeutic target in prostate cancer (PCa). BACE1 expression was observed in human PCa tissue samples, patient-derived xenografts (PDX), human PCa xenograft tissue in nude mice, and transgenic adenocarcinoma of the mouse prostate (TRAMP) tissues by immunohistochemistry (IHC) analysis. Additionally, the downstream product of BACE1 activity, i.e., Aβ1-42 expression, was also observed in these PCa tissues by IHC as well as by PET imaging in TRAMP mice. Furthermore, BACE1 gene expression and activity was confirmed in several established PCa cell lines (LNCaP, C4-2B-enzalutamide sensitive [S], C4-2B-enzalutamide resistant [R], 22Rv1-S, 22Rv1-R, PC3, DU145, and TRAMP-C1) by real-time PCR and fluorometric assay, respectively. Treatment with a pharmacological inhibitor of BACE1 (MK-8931) strongly reduced the proliferation of PCa cells in in vitro and in vivo models, analyzed by multiple assays (MTT, clonogenic, and trypan blue exclusion assays and IHC). Cell cycle analyses revealed an increase in the sub-G1 population and a significant modulation in other cell cycle stages (G1/S/G2/M) following MK-8931 treatment. Most importantly, in vivo administration of MK-8931 intraperitoneal (30 mg/kg) strongly inhibited TRAMP-C1 allograft growth in immunocompetent C57BL/6 mice (approximately 81% decrease,p= 0.019). Furthermore, analysis of tumor tissue using the prostate cancer-specific pathway array revealed the alteration of several genes involved in PCa growth and progression including Forkhead O1 (FOXO1). All together, these findings suggest BACE1 as a novel therapeutic target in advanced PCa.
近期研究表明，淀粉样前体蛋白（APP）及其β-淀粉样蛋白（Aβ）与癌症存在关联，提示β-分泌酶1（BACE1）可能在肿瘤发生过程中发挥重要作用。本研究旨在评估BACE1作为前列腺癌治疗靶点的潜在价值。通过免疫组化分析，我们在人类前列腺癌组织样本、患者来源异种移植模型、裸鼠体内人源前列腺癌异种移植组织以及转基因前列腺腺癌小鼠模型中均检测到BACE1的表达。此外，通过免疫组化及正电子发射断层扫描成像技术，在前列腺癌组织及TRAMP小鼠模型中均观察到BACE1活性下游产物Aβ1-42的表达。通过实时荧光定量PCR和荧光检测法，我们在多种已建立的前列腺癌细胞系（LNCaP、C4-2B-恩杂鲁胺敏感型[S]、C4-2B-恩杂鲁胺耐药型[R]、22Rv1-S、22Rv1-R、PC3、DU145及TRAMP-C1）中验证了BACE1基因表达及其酶活性。采用BACE1药理抑制剂（MK-8931）处理后，通过多种检测方法（MTT法、克隆形成实验、台盼蓝拒染法及免疫组化分析）证实，该抑制剂在体外和体内模型中均显著抑制前列腺癌细胞增殖。细胞周期分析显示，MK-8931处理导致亚G1期细胞比例增加，并对其他细胞周期阶段（G1/S/G2/M期）产生显著调控作用。最重要的是，在免疫正常的C57BL/6小鼠模型中腹腔注射MK-8931（30 mg/kg）可强力抑制TRAMP-C1同种移植瘤的生长（抑制率约81%，p=0.019）。通过前列腺癌特异性通路芯片对肿瘤组织进行分析，发现包括叉头框蛋白O1（FOXO1）在内的多个参与前列腺癌生长和进展的关键基因发生表达改变。综上所述，本研究提示BACE1可作为晚期前列腺癌的新型治疗靶点。
The β-Secretase 1 Enzyme as a Novel Therapeutic Target for Prostate Cancer
肿瘤(癌症)患者之家