Inhibition of pp2a activity confers a trail-sensitive phenotype during malignant transformation

Hongmei Yang, Xuanyu Chen, Xuegang Wang, Yansheng Li, Shaoyong Chen, Xiaohui Qian, Rong Wang, Li Chen, Weiwei Han, Anming Ruan, Quansheng Du, Aria F. Olumi, Xiaoping Zhang

Research output: Contribution to journalArticle

5 Scopus citations

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 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.

Original languageEnglish (US)
Pages (from-to)217-227
Number of pages11
JournalMolecular Cancer Research
Volume12
Issue number2
DOIs
StatePublished - Feb 1 2014

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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    Yang, H., Chen, X., Wang, X., Li, Y., Chen, S., Qian, X., Wang, R., Chen, L., Han, W., Ruan, A., Du, Q., Olumi, A. F., & Zhang, X. (2014). Inhibition of pp2a activity confers a trail-sensitive phenotype during malignant transformation. Molecular Cancer Research, 12(2), 217-227. https://doi.org/10.1158/1541-7786.MCR-13-0441