Antiandrogen therapy induces mitochondrial oxidative phosphorylation to promote castration resistance in prostate cancer

Tumor recurrence and therapy resistance are frequently accompanied by alterations in cellular metabolism. However, how metabolic remodeling occurs and contributes to castration-resistant prostate Cancer (CRPC) remains largely elusive. Here, we demonstrate that mitochondrial Oxidative Phosphorylation (OXPHOS) is critical for development of Androgen Receptor signaling inhibitors (ARSI) resistance. Our findings indicate that prostate Cancer cells exhibit increased mitochondrial OXPHOS following ARSI treatment. Notably, there is no significant change in glycolytic activity. Importantly, this metabolic remodeling relies on glucose and glutamine utilization. Mechanistically, ARSI treatment activates Reactive Oxygen Species/AMPK/SIRT1/PGC-1α signaling axis, leading to nuclear accumulation of PGC-1α and enhancement of mitochondrial OXHPOS and tricarboxylic acid cycle. High mitochondrial OXPHOS in turn renders prostate Cancer cells resistant to ARSI. Inhibitors of PGC-1α and mitochondrial OXPHOS restore drug sensitivity and synergize with ARSI to inhibit CRPC growth. Our findings demonstrate the metabolic plasticity of prostate Cancer cells following ARSI treatment, identifying PGC-1α/mitochondrial OXPHOS axis as a potential metabolic target for CRPC treatment.