Department of Urology, School of Medicine and Public Health, University of Wisconsin, Madison, Wisconsin, USA.
Department of Biomedical Engineering, University of Wisconsin, Madison, Wisconsin, USA.
Prostate. 2022 Dec;82(16):1547-1557. doi: 10.1002/pros.24428. Epub 2022 Aug 18.
Androgen deprivation therapy (ADT) has been the standard of care for advanced hormone-sensitive prostate cancer (PC), yet tumors invariably develop resistance resulting in castrate-resistant PC. The acute response of cancer cells to ADT includes apoptosis and cell death, but a large fraction remains arrested but viable. In this study, we focused on intensively characterizing the early metabolic changes that result after ADT to define potential metabolic targets for treatment.
A combination of mass spectrometry, optical metabolic imaging which noninvasively measures drug responses in cells, oxygen consumption rate, and protein expression analysis was used to characterize and block metabolic pathways over several days in multiple PC cell lines with variable hormone response status including ADT sensitive lines LNCaP and VCaP, and resistant C4-2 and DU145.
Mass spectrometry analysis of LNCaP pre- and postexposure to ADT revealed an abundance of glycolytic intermediates after ADT. In LNCaP and VCaP, a reduction in the optical redox ratio [NAD(P)H/FAD], extracellular acidification rate, and a downregulation of key regulatory enzymes for fatty acid and glutamine utilization was acutely observed after ADT. Screening several metabolic inhibitors revealed that blocking fatty acid oxidation and synthesis reversed this stress response in the optical redox ratio seen with ADT alone in LNCaP and VCaP. In contrast, both cell lines demonstrated increased sensitivity to the glycolytic inhibitor 2-Deoxy- d-glucose(2-DG) and maintained sensitivity to electron transport chain inhibitor Malonate after ADT exposure. ADT followed by 2-DG results in synergistic cell death, a result not seen with simultaneous administration.
Hormone-sensitive PC cells displayed altered metabolic profiles early after ADT including an overall depression in energy metabolism, induction of a quiescent/senescent phenotype, and sensitivity to selected metabolic inhibitors. Glycolytic blocking agents (e.g., 2-DG) as a sequential treatment after ADT may be promising.
去势治疗（ADT）一直是晚期激素敏感前列腺癌（PC）的标准治疗方法，但肿瘤总是会产生耐药性，导致去势抵抗性 PC。癌细胞对 ADT 的急性反应包括细胞凋亡和死亡，但仍有很大一部分细胞被阻滞但仍存活。在这项研究中，我们专注于深入描述 ADT 后导致的早期代谢变化，以确定潜在的治疗代谢靶点。
使用质谱分析、非侵入性测量细胞药物反应的光学代谢成像、耗氧量和蛋白质表达分析相结合的方法，对几种具有不同激素反应状态的 PC 细胞系（包括 ADT 敏感的 LNCaP 和 VCaP 以及耐药的 C4-2 和 DU145）进行了数天的特征描述和代谢途径阻断。
对暴露于 ADT 前后的 LNCaP 进行质谱分析，结果显示 ADT 后存在大量糖酵解中间产物。在 LNCaP 和 VCaP 中，ADT 后可观察到光学氧化还原比 [NAD(P)H/FAD]、细胞外酸化率以及脂肪酸和谷氨酰胺利用的关键调节酶表达水平降低。筛选几种代谢抑制剂发现，单独使用 ADT 时，阻断脂肪酸氧化和合成可逆转 LNCaP 和 VCaP 中光学氧化还原比的这种应激反应。相比之下，两种细胞系在 ADT 后对糖酵解抑制剂 2-脱氧-d-葡萄糖（2-DG）的敏感性增加，并且在 ADT 后对电子传递链抑制剂丙二酸的敏感性仍然存在。ADT 后再使用 2-DG 会导致协同细胞死亡，而同时给药则不会出现这种结果。
激素敏感的 PC 细胞在 ADT 后早期表现出改变的代谢特征，包括能量代谢总体下降、诱导静止/衰老表型以及对选定代谢抑制剂的敏感性。作为 ADT 后的序贯治疗，糖酵解抑制剂（如 2-DG）可能具有前景。
