Abdelwahed Khaldoun S, Siddique Abu Bakar, Qusa Mohammed H, King Judy Ann, Souid Soumaya, Abd Elmageed Zakaria Y, El Sayed Khalid A
School of Basic Pharmaceutical and Toxicological Sciences, College of Pharmacy, University of Louisiana at Monroe, 1800 Bienville Drive, Monroe, Louisiana 71201, United States.
Department of Pathology and Translational Pathobiology, LSU Health Shreveport, 1501 Kings Highway, Shreveport, Louisiana 71103, United States.
ACS Pharmacol Transl Sci. 2021 Oct 5;4(6):1771-1781. doi: 10.1021/acsptsci.1c00145. eCollection 2021 Dec 10.
Prostate cancer (PC) is the most common malignancy and the second leading cause of cancer death in men. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays an important role in the cholesterol metabolism by regulating the LDL receptor (LDLR) degradation. The PCSK9 axis is proved to be a potential novel therapeutic target in multiple cancer types. Pseurotin A (PS) is a small-molecule natural-product inhibitor of PCSK9 expression and PCSK9-LDLR protein-protein interaction (PPI). The results of this study show that PS treatments caused dose-dependent suppression of migration, colony formation, and PCSK9 expression in the PC cell lines PC-3 and 22Rv1. PS suppressed the progression of PC-3 cells orthotopically xenografted in nude mice and prevented locoregional and distant tumor recurrences after primary tumor surgical excision. Western blot analysis showed decreased PCSK9 expression in collected primary and recurred PC-3 tumors in PS-treated mice. PS treatments also reduced the hemoglobin content in collected treated tumors and the Matrigel-plug angiogenesis mouse model. PS treatments prevented metastasis to distant organs compared to vehicle-treated control mice. A reduction in mice plasma cholesterol levels was observed. Microarray analysis of collected treated primary PC-3 tumors showed a distinct gene signature that confirmed the targeting of PCSK9 and cholesterol metabolism. Thus, the PCSK9 axis is proposed as a novel PC pathogenesis molecular target, and PS is defined as a novel effective PCSK9-targeting lead potentially useful for the control of the castration-resistant PC recurrence and metastasis.
前列腺癌（PC）是男性中最常见的恶性肿瘤，也是癌症死亡的第二大主要原因。前蛋白转化酶枯草杆菌蛋白酶/kexin 9型（PCSK9）通过调节低密度脂蛋白受体（LDLR）的降解在胆固醇代谢中发挥重要作用。PCSK9轴被证明是多种癌症类型中潜在的新型治疗靶点。伪菌素A（PS）是一种小分子天然产物抑制剂，可抑制PCSK9的表达以及PCSK9-LDLR蛋白-蛋白相互作用（PPI）。本研究结果表明，PS处理导致PC细胞系PC-3和22Rv1的迁移、集落形成和PCSK9表达呈剂量依赖性抑制。PS抑制了裸鼠原位异种移植的PC-3细胞的进展，并在原发性肿瘤手术切除后预防了局部和远处肿瘤复发。蛋白质印迹分析显示，在PS处理的小鼠中，收集的原发性和复发性PC-3肿瘤中PCSK9表达降低。PS处理还降低了收集的处理后肿瘤以及基质胶栓血管生成小鼠模型中的血红蛋白含量。与载体处理的对照小鼠相比，PS处理可防止转移至远处器官。观察到小鼠血浆胆固醇水平降低。对收集的处理后的原发性PC-3肿瘤进行微阵列分析显示出独特的基因特征，证实了PCSK9和胆固醇代谢的靶向作用。因此，PCSK9轴被提议作为一种新型的PC发病机制分子靶点，PS被定义为一种新型有效的靶向PCSK9的先导物，可能对控制去势抵抗性PC的复发和转移有用。
