Liu Yongbo, Gao Xiaohua, Deeb Dorrah, Zhang Yiguan, Shaw Jiajiu, Valeriote Frederick A, Gautam Subhash C
Department of Surgery, Henry Ford Health System, Detroit, Michigan, USA.
Department of Internal Medicine, Henry Ford Health System, Detroit, Michigan, USA.
J Exp Ther Oncol. 2016 Nov;11(4):251-260.
Trichothecenes are powerful mycotoxins that inhibit protein synthesis and induce ribotoxic stress response in mammalian cells. Verrucarin A (VC-A) is a Type D macrocyclic mycotoxin which inhibits cell proliferation and induces apoptosis in cancer cells. However, the antitumor activity of VC-A for prostate cancer cells has not been investigated. The objective of the present study was to determine the anticancer activity and its mechanism of action in hormone-responsive (LNCaP) and hormone-refractory (PC-3) carcinoma of the prostate (CaP) cell lines. VC-A strongly inhibited the proliferation and induced cell cycle arrest in G2/M phase associated with the inhibition of cell cycle regulatory proteins cyclin D, cyclin E, cyclin-dependent kinases (cdks) cdk2, cdk4, cdk6 and cdk inhibitors WAF1/21 and KIP1/27. VC-A also induced apoptosis in CaP cells as characterized by the cleavage of poly (ADP-ribose) polymerase (PARP-1), procaspases-3, -8 and -9 and the inhibition of Bcl-2 family proteins that regulate apoptosis (Bcl-2, Bcl-xL, Bax, Bak and Bad). In addition, VC-A also down-regulated the expression of prosurvival phospho-AKT (p-AKT), nuclear factor kappa B (NF-kB) (p65) and phospho-mammalian target of rapamycin (p-mTOR) signaling proteins. Taken together, these results demonstrated strong antiproliferative and apoptosis-inducing activity of verrucarin A against CaP cells through cell cycle arrest and inhibition of the prosurvival (antiapoptotic) AKT/NF-kB/mTOR signaling pathway.
单端孢霉烯族毒素是一类强效霉菌毒素，可抑制蛋白质合成并在哺乳动物细胞中诱导核糖体毒性应激反应。疣孢菌素A（VC-A）是一种D型大环霉菌毒素，可抑制癌细胞增殖并诱导其凋亡。然而，VC-A对前列腺癌细胞的抗肿瘤活性尚未得到研究。本研究的目的是确定其对激素反应性（LNCaP）和激素难治性（PC-3）前列腺癌（CaP）细胞系的抗癌活性及其作用机制。VC-A强烈抑制细胞增殖，并诱导细胞周期停滞于G2/M期，这与细胞周期调节蛋白细胞周期蛋白D、细胞周期蛋白E、细胞周期蛋白依赖性激酶（cdk）cdk2、cdk4、cdk6以及cdk抑制剂WAF1/21和KIP1/27的抑制有关。VC-A还诱导CaP细胞凋亡，其特征为多聚（ADP-核糖）聚合酶（PARP-1）、前半胱天冬酶-3、-8和-9的裂解以及调节细胞凋亡的Bcl-2家族蛋白（Bcl-2、Bcl-xL、Bax、Bak和Bad）的抑制。此外，VC-A还下调了存活相关的磷酸化AKT（p-AKT）、核因子κB（NF-κB）（p65）和磷酸化哺乳动物雷帕霉素靶蛋白（p-mTOR）信号蛋白的表达。综上所述，这些结果表明疣孢菌素A通过细胞周期停滞和抑制存活相关（抗凋亡）的AKT/NF-κB/mTOR信号通路，对CaP细胞具有强大的抗增殖和诱导凋亡活性。
