Prostate cancer (PCa) often becomes drug-treatment-resistant, posing a significant challenge to effective management. Although initial treatment with androgen deprivation therapy can control advanced PCa, subsequent resistance mechanisms allow tumor cells to continue growing, necessitating alternative approaches. This study delves into the specific metabolic dependencies of different PCa subtypes and explores the potential synergistic effects of combining androgen receptor (AR) inhibition (ARN with mitochondrial complex I inhibition (IACS)). We examined the metabolic behaviors of normal prostate epithelial cells (PNT1A), androgen-sensitive cells (LNCaP and C4-2), and androgen-independent cells (PC-3) when treated with ARN, IACS, or a combination. The results uncovered distinct mitochondrial activities across PCa subtypes, with androgen-dependent cells exhibiting heightened oxidative phosphorylation (OXPHOS). The combination of ARN and IACS significantly curbed cell proliferation in multiple PCa cell lines. Cellular bioenergetics analysis revealed that IACS reduced OXPHOS, while ARN hindered glycolysis in certain PCa cells. Additionally, galactose supplementation disrupted compensatory glycolytic mechanisms induced by metabolic reprogramming. Notably, glucose-deprived conditions heightened the sensitivity of PCa cells to mitochondrial inhibition, especially in the resistant PC-3 cells. Overall, this study illuminates the intricate interplay between AR signaling, metabolic adaptations, and treatment resistance in PCa. The findings offer valuable insights into subtype-specific metabolic profiles and propose a promising strategy to target PCa cells by exploiting their metabolic vulnerabilities.
前列腺癌（PCa）常出现药物治疗耐药性，这对有效治疗构成重大挑战。虽然初始的雄激素剥夺疗法可控制晚期前列腺癌，但后续耐药机制使肿瘤细胞持续生长，亟需替代治疗方案。本研究深入探讨了不同前列腺癌亚型的特异性代谢依赖性，并探索了联合应用雄激素受体（AR）抑制剂（ARN）与线粒体复合物I抑制剂（IACS）的潜在协同效应。我们检测了正常前列腺上皮细胞（PNT1A）、雄激素敏感细胞（LNCaP和C4-2）及雄激素非依赖性细胞（PC-3）在ARN、IACS单独或联合处理下的代谢行为。结果显示不同前列腺癌亚型具有显著差异的线粒体活性，其中雄激素依赖性细胞表现出更强的氧化磷酸化（OXPHOS）能力。ARN与IACS联合用药显著抑制了多种前列腺癌细胞系的增殖。细胞生物能量学分析表明，IACS降低了OXPHOS水平，而ARN在某些前列腺癌细胞中阻碍了糖酵解过程。此外，半乳糖补充干预破坏了代谢重编程诱导的代偿性糖酵解机制。值得注意的是，葡萄糖剥夺条件增强了前列腺癌细胞对线粒体抑制的敏感性，尤其在耐药性PC-3细胞中表现显著。总体而言，本研究揭示了前列腺癌中AR信号传导、代谢适应与治疗耐药性之间复杂的相互作用机制。这些发现为理解亚型特异性代谢特征提供了重要见解，并提出通过靶向代谢脆弱性来治疗前列腺癌的潜在新策略。
肿瘤(癌症)患者之家