Antiandrogen treatment induces mitochondrial oxidative phosphorylation to promote castration resistance in prostate cancer [LNCaP]

Tumor recurrence and therapy resistance are generally accompanied by alterations in cellular metabolism. However, the mechanism by which metabolic conversion occurs and contributes to castration-resistant prostate cancer (CRPC) remains unclear. Here, we demonstrate that androgen receptor signaling inhibitors (ARSI)-induced mitochondrial oxidative phosphorylation (OXPHOS) is critical for CRPC development. Our findings indicate that prostate cancer cells exhibit increased mitochondrial OXPHOS following ARSI treatment; however, there is no significant change in glycolytic activity. Importantly, this metabolic conversion relies on increased glucose and glutamine utilization. Mechanistically, ARSI treatment induces oxidative stress, resulting in AMPK/PGC-1α-dependent metabolic conversion. High mitochondrial OXPHOS in turn renders prostate cancer cells resistant to ARSI. Pharmacological inhibition of mitochondrial OXPHOS shows promising treatment efficacy for CRPC and synergizes with ARSI to inhibit CRPC growth. Collectively, we demonstrate the metabolic plasticity of prostate cancer cells following ARSI treatment, identifying mitochondrial OXPHOS as a metabolic target for CRPC treatment.