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Pleckstrin-2 Mediates the Activation of AKT in Prostate Cancer and Is Repressed by Androgen Receptor

Xu Han1, Ali Zhang1, Pan Wang1

  • 1Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois; Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, Illinois.

The American Journal of Pathology
|July 28, 2024
PubMed

Insights

Pleckstrin-2 (PLEK2) connects prostate cancer's PI3K-AKT and androgen receptor pathways. Targeting PLEK2 inhibits cancer cell proliferation, offering a new therapeutic strategy for advanced prostate cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Prostate cancer often involves activated Phosphoinositide 3-kinase (PI3K)-AKT and androgen receptor (AR) pathways.
  • The complex interplay between these pathways complicates treatment for advanced prostate cancer.

Purpose of the Study:

  • To investigate the role of pleckstrin-2 (PLEK2) in connecting the PI3K-AKT and AR pathways in prostate cancer.
  • To explore PLEK2 as a potential therapeutic target for prostate cancer treatment.

Main Methods:

  • Utilized genetic manipulation (Plek2 deficiency, PLEK2 overexpression, AR knockdown) in mouse models and prostate cancer cell lines.
  • Investigated the regulatory relationship between AR and PLEK2 at the transcriptional level.
  • Assessed the effect of a PLEK2 inhibitor on prostate cancer cell proliferation and AKT pathway activity.

Main Results:

  • Plek2 deficiency reversed tumorigenesis in Pten-deficient mice; PLEK2 overexpression promoted prostate cancer cell proliferation in vitro.
  • AR transcriptionally repressed PLEK2, creating a reciprocal inhibitory loop.
  • AR overexpression inactivated AKT, while AR knockdown activated it via PLEK2.
  • A PLEK2 inhibitor reduced prostate cancer cell proliferation and inactivated AKT.

Conclusions:

  • PLEK2 acts as a crucial link between the PI3K-AKT and AR pathways in prostate cancer.
  • Targeting PLEK2 pharmacologically presents a viable strategy for treating prostate cancer by inhibiting proliferation and inactivating AKT.

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