Ectopic FGFR1 Increases Intracellular Pool of Cholesterol in Prostate Cancer Cells

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Prostate cancer (PCa) is a leading male cancer, often treated with androgen deprivation therapy (ADT).
• Most PCa progresses to castration-resistant PCa (CRPC) due to mechanisms like cholesterol-driven steroidogenesis.
• Low-density lipoprotein (LDL) uptake is a key source of cholesterol for PCa cells, but its regulation is unclear.

Purpose of the Study:

• To investigate the role of fibroblast growth factor receptor 1 (FGFR1) in regulating cholesterol metabolism in PCa.
• To identify therapeutic targets for overcoming ADT resistance in PCa.

Main Methods:

• Generated FGFR1-null DU145 cells and performed comparative transcriptome analysis.
• Conducted mechanistic studies on FGFR1 signaling pathways, including sterol regulatory element-binding protein 2 (SREBP2) activation.
• Performed in silico analyses correlating FGFR1 expression with clinical data.

Main Results:

• FGFR1 ablation reduced expression of genes involved in LDL uptake and cholesterol synthesis, decreasing cellular cholesterol.
• FGFR1 enhances SREBP2 activation via ERK signaling, upregulating LDL receptor (LDLR) and cholesterol synthesis enzymes.
• High FGFR1 expression correlates with high LDLR expression and adverse clinicopathological features in PCa.

Conclusions:

• FGFR1 plays a critical role in regulating cholesterol homeostasis in PCa cells.
• Targeting FGFR1 represents a novel therapeutic strategy for CRPC by inhibiting cholesterol uptake and synthesis.