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Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
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Pristimerin-induced uveal melanoma cell death via inhibiting PI3K/Akt/FoxO3a signalling pathway

Fengxia Yan1,2, Rifang Liao1,3, Marta Silva1

  • 1Faculty of Health Sciences, University of Macau, Macau, China.

Journal of Cellular and Molecular Medicine
|April 30, 2020
PubMed

Insights

Pristimerin, a natural compound, effectively inhibits uveal melanoma (UM) cell migration and invasion. It induces apoptotic cell death by targeting the PI3K/Akt/FoxO3a pathway, suggesting its potential as a UM chemotherapeutic agent.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Uveal melanoma (UM) is an aggressive eye cancer with limited treatment options for metastatic disease.
  • Pristimerin, a triterpenoid compound, exhibits anti-cancer properties but its effect on UM is largely unexplored.
  • There is a critical need for novel therapeutic strategies against metastatic UM.

Purpose of the Study:

  • To investigate the cytotoxic effects of Pristimerin on uveal melanoma cells.
  • To elucidate the underlying molecular mechanisms of Pristimerin's action in UM.
  • To evaluate Pristimerin's potential as a chemotherapeutic agent for UM.

Main Methods:

  • Treatment of UM-1 cells with Pristimerin.
  • Assessment of cell migration, invasion, reactive oxygen species (ROS) levels, and mitochondrial membrane potential.
  • Cell cycle analysis and apoptosis assays.
  • Western blot analysis to evaluate protein expression and phosphorylation.
  • Pharmacological inhibition and siRNA knockdown of key pathway proteins (PI3K, Akt, FoxO3a).

Main Results:

  • Pristimerin significantly inhibited UM-1 cell migration and invasion.
  • Pristimerin induced ROS production, decreased mitochondrial membrane potential, and caused G0/G1 cell cycle arrest, leading to apoptosis.
  • Pristimerin suppressed Akt and FoxO3a phosphorylation, promoting FoxO3a nuclear accumulation.
  • Upregulation of pro-apoptotic proteins (Bim, p27Kip1, cleaved caspase-3, PARP, Bax) and downregulation of anti-apoptotic proteins (Cyclin D1, Bcl-2) were observed.
  • Inhibition of the PI3K/Akt/FoxO3a pathway potentiated Pristimerin-induced apoptosis, while FoxO3a knockdown partially abolished its effects.

Conclusions:

  • Pristimerin induces apoptotic cell death in UM-1 cells via the PI3K/Akt/FoxO3a signaling pathway.
  • Pristimerin demonstrates significant anti-migratory and anti-invasive properties in UM cells.
  • These findings support Pristimerin as a promising candidate for the development of novel chemotherapeutic treatments for uveal melanoma.
Keywords:
FoxO3aPristimerincell deathnuclear accumulationuveal melanoma

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