2,4-dienoyl-CoA reductase regulates lipid homeostasis in treatment-resistant prostate cancer

Area of Science:

• Oncology
• Molecular Biology
• Metabolomics

Background:

• Androgen Receptor (AR)-targeted therapies are clinically successful for prostate cancer.
• Reactivation of AR signaling drives castration-resistant prostate cancer (CRPC) progression.
• Understanding resistance mechanisms is crucial for improving CRPC treatment.

Purpose of the Study:

• To comprehensively characterize LNCaP cells resistant to AR inhibitors (ARI).
• To identify key proteins and metabolic alterations associated with ARI resistance.
• To evaluate the therapeutic potential of targeting identified resistance mechanisms in CRPC.

Main Methods:

• Proteomics and metabolomics analyses of LNCaP cells under chronic ARI exposure.
• Identification and validation of proteins associated with ARI resistance.
• Functional studies including gene knockout (DECR1) and in vivo tumor growth assays.

Main Results:

• ARI-resistant cells exhibit an acquired metabolic phenotype with perturbed glucose and lipid metabolism.
• Mitochondrial 2,4-dienoyl-CoA reductase (DECR1) is identified as a clinically relevant biomarker for CRPC.
• DECR1 knockout induces ER stress, sensitizes cells to ferroptosis, impairs lipid metabolism, and reduces tumor growth in vivo.

Conclusions:

• Metabolic adaptation, particularly involving lipid metabolism, is a key driver of AR inhibitor resistance in CRPC.
• DECR1 plays a critical role in maintaining redox homeostasis and promoting CRPC progression.
• Targeting DECR1 represents a potential therapeutic strategy for overcoming treatment resistance in CRPC.