Cholesterol Auxotrophy as a Targetable Vulnerability in Clear Cell Renal Cell Carcinoma

Area of Science:

• Oncology
• Metabolic pathways
• Lipid metabolism

Background:

• Clear cell renal cell carcinoma (ccRCC) exhibits significant intracellular cholesterol accumulation.
• The functional role of this cholesterol excess in ccRCC pathogenesis remains unclear.
• Genes for cholesterol biosynthesis are downregulated in ccRCC, suggesting reliance on external sources.

Purpose of the Study:

• To investigate the functional significance of cholesterol in ccRCC.
• To explore the link between high-density lipoprotein (HDL) cholesterol and ccRCC risk.
• To identify potential therapeutic targets related to cholesterol metabolism in ccRCC.

Main Methods:

• Mendelian randomization analyses in 31,000 individuals.
• In vitro and in vivo experiments involving cholesterol and HDL deprivation/supplementation in ccRCC cells.
• Inhibition of Scavenger Receptor B1 (SCARB1) and assessment of downstream signaling pathways (PI3K/AKT) and reactive oxygen species (ROS).

Main Results:

• Elevated circulating HDL cholesterol causally linked to increased ccRCC risk.
• ccRCC cell proliferation, survival, and tumor growth are compromised by cholesterol or HDL deprivation.
• Inhibition of SCARB1 induces ccRCC cell-cycle arrest, apoptosis, increased ROS, and decreased PI3K/AKT signaling.
• Elevated dietary cholesterol promotes ccRCC tumor growth.

Conclusions:

• ccRCC cells exhibit auxotrophy for exogenous cholesterol, crucial for maintaining PI3K/AKT signaling and ROS homeostasis.
• SCARB1 is essential for cholesterol import in ccRCC.
• Targeting SCARB1 represents a promising therapeutic strategy for kidney cancer.