Adipose Triglyceride Lipase Is a Therapeutic Target in Advanced Prostate Cancer That Promotes Metabolic Plasticity

Area of Science:

• Oncology
• Metabolic pathways
• Lipid metabolism

Background:

• Lipid metabolism is crucial in prostate cancer, but current strategies targeting lipogenesis and uptake have limited clinical success.
• Understanding how cancer cells utilize stored lipids is key to developing novel therapeutic approaches.

Purpose of the Study:

• To investigate the role of adipose triglyceride lipase (ATGL) in prostate cancer progression.
• To evaluate ATGL as a potential therapeutic target for castration-resistant prostate cancer (CRPC).

Main Methods:

• Correlating ATGL expression with patient survival data.
• Inhibiting ATGL using molecular, genetic, and pharmacologic approaches in preclinical models (in vitro and in vivo).
• Utilizing mass spectrometry imaging and phosphoproteomics to analyze lipid metabolism and signaling pathways.

Main Results:

• Elevated ATGL expression correlates with worse survival in advanced CRPC patients.
• ATGL inhibition significantly impaired prostate cancer growth in various models.
• ATGL regulates in vivo lipid metabolism and remodeling of membrane composition.
• ATGL inhibition induced a metabolic shift towards glycolysis, suggesting a vulnerability for combination therapies.
• A specific ATGL mutation (serine 404) impaired CRPC progression independently of its lipolytic activity, highlighting noncanonical functions.

Conclusions:

• ATGL is a critical driver of prostate cancer progression through both lipase-dependent and independent mechanisms.
• Targeting ATGL presents a promising therapeutic strategy for CRPC.
• Further research into ATGL's noncanonical functions and its role in metabolic plasticity can inform the development of novel combination therapies.