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Inhibition of PP2A activity confers a TRAIL-sensitive phenotype during malignant transformation

Hongmei Yang1, Xuanyu Chen, Xuegang Wang

  • 1Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, Hubei Province, China. xiaoping.zhang2008@gmail.com.

Molecular Cancer Research : MCR
|December 4, 2013
PubMed
Abstract

Insights

Inhibition of protein phosphatase 2A (PP2A) sensitizes normal cells to TRAIL-induced apoptosis during tumorigenesis. This PP2A inhibition, mediated by c-Fos/AP-1, is crucial for cancer cells to become sensitive to TRAIL therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • TRAIL (TNF-related apoptosis-inducing ligand) induces apoptosis in cancer cells but spares normal cells.
  • Understanding how normal cells gain TRAIL sensitivity during malignant transformation is key to improving cancer therapies.

Purpose of the Study:

  • To elucidate the mechanism by which normal cells acquire TRAIL sensitivity during tumorigenesis.
  • To investigate the role of protein phosphatase 2A (PP2A) in this process.

Main Methods:

  • Developed a cell model by introducing human telomerase reverse transcriptase and SV40 T antigens into normal human prostatic epithelial cells (PrEC).
  • Inhibited PP2A using SV40 small T antigen, okadaic acid, Calyculin A, or siRNA.
  • Assessed TRAIL-induced apoptosis and analyzed the regulation of c-Fos/AP-1.

Main Results:

  • PP2A inhibition sensitized normal PrEC and immortalized cells to TRAIL-induced apoptosis.
  • This sensitization occurred during the premalignant stage of tumorigenesis.
  • PP2A negatively regulated c-Fos/AP-1, mediating its antiapoptotic activity.
  • Low-dose okadaic acid sensitized TRAIL-resistant cancer cells to TRAIL.

Conclusions:

  • Downregulation of PP2A activity is critical for normal cells to become TRAIL-sensitive during tumorigenesis.
  • PP2A inhibition, via c-Fos/AP-1, is a key determinant of TRAIL sensitivity.
  • PP2A inhibitors may enhance TRAIL-based cancer therapies.

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