Cell Death Signaling Laboratory, Division of Science (Biology), Experimental Research Building, New York University Abu Dhabi, P.O. Box 129188, Saadiyat Island Campus, Abu Dhabi, United Arab Emirates.
Cancer Lett. 2018 Jul 10;426:80-97. doi: 10.1016/j.canlet.2018.04.009. Epub 2018 Apr 12.
Thymoquinone (TQ), the predominant bioactive constituent present in black cumin (Nigella sativa), exerts tumor suppressive activity against a wide variety of cancer cells. Cellular senescence, characterized by stable and long term loss of proliferative capacity, acts as a potent tumor suppressive mechanism. Here, we provide evidence for the first time that TQ suppresses growth of glioma cells by potentially inducing the expression of prostate apoptosis response-4 (Par-4) tumor suppressor protein. In turn, TQ-induced Par-4 expression triggers cellular senescence, as evidenced by increasing cellular size, β-galactosidase staining, G1 phase arrest, and increased expression of senescence markers such as p53, p21, Rb, and decreased expression of lamin B1, cyclin E and cyclin depended kinase-2 (CDK-2). Further, overexpression of Par-4 significantly increases the expression of p53 and its downstream target p21, and increases β-galactosidase positive cells, while siRNA/shRNA mediated-knockdown of Par-4 reverses the TQ-induced effects. Altogether, we describe a novel mechanism of cross talk between Par-4 and p53, that plays a critical role in TQ-induced senescence in human malignant glioma cells.
姜黄色素（TQ）是黑孜然（Nigella sativa）中主要的生物活性成分，对多种癌细胞具有肿瘤抑制活性。细胞衰老的特征是增殖能力的稳定和长期丧失，它是一种有效的肿瘤抑制机制。在这里，我们首次提供证据表明，TQ 通过潜在地诱导前列腺凋亡反应蛋白 4（Par-4）肿瘤抑制蛋白的表达来抑制神经胶质瘤细胞的生长。反过来，TQ 诱导的 Par-4 表达触发细胞衰老，这表现在细胞体积增大、β-半乳糖苷酶染色、G1 期停滞以及衰老标志物如 p53、p21、Rb 的表达增加，而层粘连蛋白 B1、细胞周期蛋白 E 和细胞周期依赖性激酶-2（CDK-2）的表达减少。此外，Par-4 的过表达显著增加了 p53 及其下游靶标 p21 的表达，并增加了β-半乳糖苷酶阳性细胞，而 Par-4 的 siRNA/shRNA 介导的敲低逆转了 TQ 诱导的作用。总之，我们描述了 Par-4 和 p53 之间的一种新的串扰机制，在 TQ 诱导的人类恶性神经胶质瘤细胞衰老中起关键作用。
