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Inhibition of Pten deficient Castration Resistant Prostate Cancer by Targeting of the SET - PP2A Signaling axis

Xiaoyong Hu1,2, Consuelo Garcia2, Ladan Fazli3

  • 1The 6th People's Hospital, Shanghai Jiaotong University, Shanghai, 200233, China.

Scientific Reports
|November 14, 2015
PubMed

Insights

Targeting the SET-PP2A pathway inhibits castration-resistant prostate cancer (CRPC). This study shows SET overexpression drives CRPC, and inhibiting it with OP449 halts tumor growth and progression.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • The PP2A signaling pathway is crucial in regulating oncogenic drivers of castration-resistant prostate cancer (CRPC).
  • SET (I2PP2A) is an endogenous regulator of PP2A, implicated in cancer progression.

Purpose of the Study:

  • To investigate the role of the SET-PP2A signaling axis in CRPC.
  • To evaluate SET as a therapeutic target and the efficacy of PP2A-activating drugs (PADs) like OP449 in CRPC models.

Main Methods:

  • Analysis of prostate cancer patient cohorts for SET transcript levels.
  • Tissue microarray analysis to correlate SET expression with clinical parameters.
  • Prostate regeneration assays to assess the in vivo effects of SET overexpression.
  • In vivo and in vitro studies using SET knockdown models.
  • In vitro and in vivo treatment with OP449 in CRPC cell lines and mouse models (Pten conditional deletion).

Main Results:

  • Elevated SET transcripts and expression correlate with higher cancer grading, NHT duration, and recurrence in CRPC patients.
  • In vivo SET overexpression induced prostatic hyperplasia and intraepithelial neoplasia.
  • SET knockdown significantly reduced tumorgenesis in murine and human xenograft models.
  • OP449 demonstrated anti-cancer effects in enzalutamide-resistant prostate cancer cell lines.
  • OP449 inhibited PI3K-Akt signaling and impeded CRPC progression in the Pten conditional deletion mouse model.

Conclusions:

  • The SET-PP2A signaling axis plays a critical role in CRPC progression and hormone-resistant disease.
  • Targeting SET, or activating PP2A with drugs like OP449, represents a viable therapeutic strategy for CRPC.

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