Solid tumors are highly reliant on lipids for energy, growth, and survival. In prostate cancer, the activity of the androgen receptor (AR) is associated with reprogramming of lipid metabolic processes. Here, we identified acyl-CoA synthetase medium chain family members 1 and 3 (ACSM1 and ACSM3) as AR-regulated mediators of prostate cancer metabolism and growth. ACSM1 and ACSM3 were upregulated in prostate tumors compared to non-malignant tissues and other cancer types. Both enzymes enhanced proliferation and protected prostate cancer cells from death in vitro, while silencing ACSM3 led to reduced tumor growth in an orthotopic xenograft model. ACSM1 and ACSM3 were major regulators of the prostate cancer lipidome and enhanced energy production via fatty acid oxidation. Metabolic dysregulation caused by loss of ACSM1/3 led to mitochondrial oxidative stress, lipid peroxidation and cell death by ferroptosis. Conversely, elevated ACSM1/3 activity enabled prostate cancer cells to survive toxic levels of medium chain fatty acids and promoted resistance to ferroptosis-inducing drugs and AR antagonists. Collectively, this study reveals a tumor-promoting function for medium chain acyl-CoA synthetases and positions ACSM1 and ACSM3 as key players in prostate cancer progression and therapy resistance.

中文翻译：

---

ACSM1 和 ACSM3 调节脂肪酸代谢以支持前列腺癌生长并抑制铁死亡

实体瘤的能量、生长和存活高度依赖脂质。在前列腺癌中，雄激素受体 (AR) 的活性与脂质代谢过程的重编程相关。在这里，我们鉴定了酰基辅酶A合成酶中链家族成员1和3（ACSM1和ACSM3）作为前列腺癌代谢和生长的AR调节介质。与非恶性组织和其他癌症类型相比，ACSM1 和 ACSM3 在前列腺肿瘤中表达上调。这两种酶都能在体外增强增殖并保护前列腺癌细胞免于死亡，而沉默 ACSM3 会导致原位异种移植模型中肿瘤生长减少。 ACSM1 和 ACSM3 是前列腺癌脂质组的主要调节因子，并通过脂肪酸氧化增强能量产生。 ACSM1/3 缺失引起的代谢失调导致线粒体氧化应激、脂质过氧化和铁死亡引起的细胞死亡。相反，ACSM1/3 活性升高使前列腺癌细胞能够在中链脂肪酸的毒性水平下存活，并促进对铁死亡诱导药物和 AR 拮抗剂的抵抗。总的来说，这项研究揭示了中链酰基辅酶A合成酶的促肿瘤功能，并将 ACSM1 和 ACSM3 定位为前列腺癌进展和治疗耐药的关键参与者。