Mycotoxin verrucarin A inhibits proliferation and induces apoptosis in prostate cancer cells by inhibiting prosurvival Akt/NF-kB/mTOR signaling.
Mycotoxin verrucarin A inhibits proliferation and induces apoptosis in prostate cancer cells by inhibiting prosurvival Akt/NF-kB/mTOR signaling.
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发表时间：
2016-11
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通讯作者：
Yongbo Liu;Xiaohua Gao;D. Deeb;Yiguan Zhang;J. Shaw;F. Valeriote;S. Gautam
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作者：
Yongbo Liu;Xiaohua Gao;D. Deeb;Yiguan Zhang;J. Shaw;F. Valeriote;S. Gautam
单端孢霉烯类是一种强有力的真菌毒素，能抑制哺乳动物细胞的蛋白质合成并诱导核糖毒性应激反应。疣孢菌素A（Verrucarin A，VC-A）是一种D型大环真菌毒素，具有抑制细胞增殖和诱导肿瘤细胞凋亡的作用。然而，尚未研究VC-A对前列腺癌细胞的抗肿瘤活性。本研究的目的是确定在前列腺癌细胞系中的抗肿瘤活性及其作用机制。VC-A可明显抑制细胞增殖，并诱导细胞周期阻滞于G2/M期，这与其抑制细胞周期调控蛋白cyclin D、cyclin E、细胞周期蛋白依赖性激酶（cyclin-dependent kinases，cdks）cdk 2、cdk 4、cdk 6和cdk抑制剂WAF 1/21和KIP 1/27有关。VC-A还诱导CaP细胞中的凋亡，其特征在于裂解聚（ADP-核糖）聚合酶（PARP-1）、半胱氨酸蛋白酶原-3、-8和-9以及抑制调节凋亡的Bcl-2家族蛋白（Bcl-2、Bcl-xL、Bax、巴克和Bad）。此外，VC-A还下调促生存磷酸化AKT（p-AKT）、核因子kappa B（NF-kB）（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通过细胞周期阻滞和抑制促存活（抗凋亡）AKT/NF-κ B/mTOR信号通路对CaP细胞具有强的抗增殖和凋亡诱导活性。
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.