Inhibition of PP2A Activity Confers a TRAIL-Sensitive Phenotype during Malignant Transformation
Inhibition of PP2A Activity Confers a TRAIL-Sensitive Phenotype during Malignant Transformation
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DOI：
10.1158/1541-7786.mcr-13-0441
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发表时间：
2013-12
影响因子：
5.2
通讯作者：
Hongmei Yang;X. Chen;Xuegang Wang;YAN-SHA Li;Shaoyong Chen;Xiaohui Qian;Rong Wang;Li Chen;Weiwei Han;A. Ruan;Q. Du;A. Olumi;Xiaoping Zhang
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文献类型：
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作者：
Hongmei Yang;X. Chen;Xuegang Wang;YAN-SHA Li;Shaoyong Chen;Xiaohui Qian;Rong Wang;Li Chen;Weiwei Han;A. Ruan;Q. Du;A. Olumi;Xiaoping Zhang
TRAIL是一种很有前途的抗癌药物，因为它可以诱导大多数人类癌细胞的凋亡，而不会导致正常细胞的凋亡。为了探讨正常细胞在癌变过程中如何获得TRAIL敏感表型的机制，将人端粒酶逆转录酶和SV40T抗原(大小)依次导入正常前列腺上皮细胞(PREC)，建立了一个实验细胞系统。该模型系统表明，SV40小T抗原、冈田酸、Calyculin A或PP2A催化亚基siRNA对蛋白磷酸酶2A(PP2A)的抑制都能使正常人前EC和永生化细胞对TRAIL诱导的细胞凋亡敏感。此外，致敏作用发生在肿瘤发生前阶段，PP2A通过负调控c-Fos/AP-1发挥其抗细胞凋亡作用。此外，低剂量冈田酸处理使TRAIL耐药癌细胞对TRAIL增敏，提示PP2A抑制剂可作为TRAIL或TRAIL样药诱导的细胞凋亡的增强剂。这些数据表明，PP2A活性下调是正常细胞在肿瘤发生过程中获得TRAIL敏感表型的关键步骤，PP2A活性水平可能预示着细胞对TRAIL诱导的细胞凋亡的敏感性。提示：抑制PP2A是肿瘤发生过程中获得TRAIL敏感性的关键决定因素，c-Fos/AP-1是重要的介导物。摩尔癌症资源；12(2)；217-27。©2013 AACR。
TRAIL is a promising anticancer agent because it induces apoptosis in the majority of human cancer cells but spares the normal cells. To determine the mechanistic nature of how normal cells acquire a TRAIL-sensitive phenotype during the process of malignant transformation, an experimental cell system was developed by sequential introduction of human telomerase reverse transcriptase and SV40 T antigens (large and small) into normal human prostatic epithelial cells (PrEC). This model system demonstrated that inhibition of protein phosphatase 2A (PP2A), either by SV40 small T antigen, okadaic acid, Calyculin A, or PP2A catalytic subunit siRNA, sensitized normal human PrEC and immortalized cells to TRAIL-induced apoptosis. Moreover, sensitization occurred during the premalignant period of tumorigenesis and PP2A exerted its antiapoptotic activity by negatively regulating c-Fos/AP-1. In addition, low-dose okadaic acid treatment sensitized TRAIL-resistant cancer cells to TRAIL, suggesting that PP2A inhibitors could be used as an enhancer of apoptosis induced by TRAIL or TRAIL-like agents. These data indicate that downregulation of PP2A activity is a critical step for normal cells to acquire a TRAIL-sensitive phenotype during tumorigenesis and that the level of PP2A activity may foretell cellular sensitivity to TRAIL-induced apoptosis. Implications: Inhibition of PP2A is a key determinant in acquiring TRAIL sensitivity during tumorigenesis, with c-Fos/AP-1 as an essential mediator. Mol Cancer Res; 12(2); 217–27. ©2013 AACR.