TY - JOUR
T1 - Inhibition of pp2a activity confers a trail-sensitive phenotype during malignant transformation
AU - Yang, Hongmei
AU - Chen, Xuanyu
AU - Wang, Xuegang
AU - Li, Yansheng
AU - Chen, Shaoyong
AU - Qian, Xiaohui
AU - Wang, Rong
AU - Han, Weiwei
AU - Ruan, Anming
AU - Du, Quansheng
AU - Olumi, Aria F.
AU - Zhang, Xiaoping
PY - 2014/2
Y1 - 2014/2
N2 - 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 TRAILinduced 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.
AB - 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 TRAILinduced 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.
UR - http://www.scopus.com/inward/record.url?scp=84896707863&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84896707863&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-13-0441
DO - 10.1158/1541-7786.MCR-13-0441
M3 - Article
C2 - 24296757
AN - SCOPUS:84896707863
SN - 1541-7786
VL - 12
SP - 217
EP - 227
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 2
ER -