Kranzbühler Benedikt, Salemi Souzan, Umbricht Christoph A, Müller Cristina, Burger Irene A, Sulser Tullio, Eberli Daniel
Department of Urology, Laboratory for Tissue Engineering and Stem Cell Therapy, University Hospital Zürich, Zürich, Switzerland.
Center for Radiopharmaceutical Sciences ETH-PSI-USZ, Paul Scherrer Institut, Villigen-PSI, Switzerland.
Prostate. 2018 Jul;78(10):758-765. doi: 10.1002/pros.23522. Epub 2018 Apr 6.
Prostate-specific membrane antigen (PSMA)-based imaging and therapy are increasingly used for prostate cancer management. However, limitations are a low PSMA expression in certain patients. Androgen receptor axis inhibition can induce PSMA expression in vitro. We hypothesized that different approved compounds upregulate PSMA expression and tested their effect in vitro.
Androgen receptor (AR) expressing prostate cancer (LNCaP) and epithelial prostate cells (PNT1A) were treated for 7 days with enzalutamide, dutasteride, rapamycin, metformin, lovastatin, and acetylsalicylic acid (ASA). PSMA and AR protein expression was assessed using flow cytometry, immunocytochemistry and immunoblotting. Furthermore, uptake and internalization of Lu-PSMA-617 was performed.
Enzalutamide and dutasteride led to a significant (both P < 0.05) upregulation of PSMA surface levels in LNCaP cells. In addition, treatment with rapamycin showed a non-significant trend toward PSMA upregulation. No changes were detected after treatment with vehicle, metformin, lovastatin, and ASA. Total PSMA protein expression was significantly enhanced after treatment with enzalutamide and rapamycin (both P < 0.05), whereas dutasteride led to a non-significant upregulation. Uptake of Lu-PSMA-617 was significantly increased after treatment of LNCaP with enzalutamide, dutasteride, and rapamycin (P < 0.05). In addition, internalization was significantly increased by enzalutamide and rapamycin (P < 0.05), and non-significantly increased by dutasteride.
In conclusion, our data provide new insights into the effect of different approved pharmacological compounds that can markedly upregulate PSMA expression and radioligand uptake in vitro. Pharmacologically induced PSMA expression may prove useful to improve prostate cancer detection and to enhance anticancer effects in PSMA-based therapy.
基于前列腺特异性膜抗原（PSMA）的成像和治疗越来越多地用于前列腺癌的管理。然而，局限性在于某些患者中PSMA表达较低。雄激素受体轴抑制可在体外诱导PSMA表达。我们假设不同的已批准化合物可上调PSMA表达，并在体外测试了它们的作用。
用恩杂鲁胺、度他雄胺、雷帕霉素、二甲双胍、洛伐他汀和乙酰水杨酸（ASA）处理表达雄激素受体（AR）的前列腺癌（LNCaP）和前列腺上皮细胞（PNT1A）7天。使用流式细胞术、免疫细胞化学和免疫印迹评估PSMA和AR蛋白表达。此外，进行了Lu-PSMA-617的摄取和内化实验。
恩杂鲁胺和度他雄胺导致LNCaP细胞中PSMA表面水平显著上调（均P<0.05）。此外，雷帕霉素处理显示出PSMA上调的非显著趋势。用载体、二甲双胍、洛伐他汀和ASA处理后未检测到变化。恩杂鲁胺和雷帕霉素处理后总PSMA蛋白表达显著增强（均P<0.05），而度他雄胺导致非显著上调。用恩杂鲁胺、度他雄胺和雷帕霉素处理LNCaP后，Lu-PSMA-617的摄取显著增加（P<0.05）。此外，恩杂鲁胺和雷帕霉素显著增加了内化（P<0.05），度他雄胺非显著增加。
总之，我们的数据为不同已批准的药理化合物的作用提供了新的见解，这些化合物可在体外显著上调PSMA表达和放射性配体摄取。药理诱导的PSMA表达可能有助于改善前列腺癌检测，并增强基于PSMA的治疗中的抗癌效果。
