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Targeting the PLK1-FOXO1 pathway as a novel therapeutic approach for treating advanced prostate cancer

Lilia Gheghiani1, Shengzhe Shang1, Zheng Fu2

  • 1Department of Human and Molecular Genetics, VCU Institute of Molecular Medicine, VCU Massey Cancer Center, School of Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA.

Scientific Reports
|July 25, 2020
PubMed

Insights

Restoring the tumor suppressor FOXO1

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Biology

Background:

  • Forkhead box protein O1 (FOXO1) acts as a tumor suppressor involved in apoptosis and cell cycle arrest.
  • FOXO1 inactivation is common in human cancers, suggesting its restoration could be a therapeutic strategy.
  • Polo-like kinase 1 (PLK1) regulates FOXO1 activity during the cell cycle.

Purpose of the Study:

  • To investigate if restoring FOXO1's pro-apoptotic activity can be a novel cancer treatment strategy.
  • To explore the role of PLK1 in regulating FOXO1 activity in prostate cancer.
  • To evaluate the therapeutic potential of targeting the PLK1-FOXO1 pathway in advanced prostate cancer.

Main Methods:

  • Investigated PLK1-dependent phosphorylation of FOXO1 in prostate cancer cells.
  • Assessed the impact of blocking PLK1-mediated phosphorylation on FOXO1 activity.
  • Evaluated the combined effects of PLK1 inhibition and nocodazole treatment on prostate cancer cells in vitro.

Main Results:

  • PLK1-dependent phosphorylation causes FOXO1 nuclear exclusion and reduces its transcriptional activity in prostate cancer.
  • Blocking PLK1-mediated phosphorylation reactivated FOXO1's pro-apoptotic function in prostate cancer.
  • Combined PLK1 inhibition and nocodazole treatment showed synergistic antitumor effects with minimal toxicity to normal cells.

Conclusions:

  • Targeting the PLK1-FOXO1 pathway offers a novel approach to reactivate apoptosis in advanced prostate cancer.
  • Inhibition of PLK1 can restore the tumor-suppressive functions of FOXO1.
  • This strategy holds promise for treating advanced prostate cancer by targeting key cell cycle and apoptosis regulators.

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