title: Inhibition of PP2A activity confers a TRAIL-sensitive phenotype during malignant transformation.
abstract: 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.
  
  
  CONCLUSIONS
  Inhibition of PP2A is a key determinant in acquiring TRAIL sensitivity during tumorigenesis, with c-Fos/AP-1 as an essential mediator.
authors.affiliation: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, China. xiaoping.zhang2008@gmail.com.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Yang
authors.forename: Xuanyu
authors.initials: X
authors.lastname: Chen
authors.forename: Xuegang
authors.initials: X
authors.lastname: Wang
authors.forename: Yansheng
authors.initials: Y
authors.lastname: Li
authors.forename: Shaoyong
authors.initials: S
authors.lastname: Chen
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Qian
authors.forename: Rong
authors.initials: R
authors.lastname: Wang
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Weiwei
authors.initials: W
authors.lastname: Han
authors.forename: Anming
authors.initials: A
authors.lastname: Ruan
authors.forename: Quansheng
authors.initials: Q
authors.lastname: Du
authors.forename: Aria F
authors.initials: AF
authors.lastname: Olumi
authors.forename: Xiaoping
authors.initials: X
authors.lastname: Zhang
mesh_terms: D000952:Antigens, Polyomavirus Transforming / Q000494:pharmacology; D017209:Apoptosis; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D004847:Epithelial Cells / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D008387:Marine Toxins; D019319:Okadaic Acid / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology; D010641:Phenotype; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D034741:RNA, Small Interfering / Q000494:pharmacology; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism; D019098:Telomerase
chemical_list: D000952:Antigens, Polyomavirus Transforming; D004791:Enzyme Inhibitors; D008387:Marine Toxins; D010080:Oxazoles; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D019319:Okadaic Acid; C059041:calyculin A; C509186:TERT protein, human; D019098:Telomerase; D054648:Protein Phosphatase 2