Discipline of Physiology, School of Medical Sciences & Bosch Institute, Charles Perkins Centre, Faculty of Medicine and Health, The University of Sydney, New South Wales, Australia.
Adelaide Medical School and Freemasons Foundation Centre for Men's Health, University of Adelaide, Adelaide, South Australia, Australia.
Mol Cancer Res. 2019 Apr;17(4):949-962. doi: 10.1158/1541-7786.MCR-18-0347. Epub 2019 Jan 15.
Prostate cancer cells exhibit altered cellular metabolism but, notably, not the hallmarks of Warburg metabolism. Prostate cancer cells exhibit increased synthesis of fatty acids (FA); however, little is known about how extracellular FAs, such as those in the circulation, may support prostate cancer progression. Here, we show that increasing FA availability increased intracellular triacylglycerol content in cultured patient-derived tumor explants, LNCaP and C4-2B spheroids, a range of prostate cancer cells (LNCaP, C4-2B, 22Rv1, PC-3), and prostate epithelial cells (PNT1). Extracellular FAs are the major source (∼83%) of carbons to the total lipid pool in all cell lines, compared with glucose (∼13%) and glutamine (∼4%), and FA oxidation rates are greater in prostate cancer cells compared with PNT1 cells, which preferentially partitioned extracellular FAs into triacylglycerols. Because of the higher rates of FA oxidation in C4-2B cells, cells remained viable when challenged by the addition of palmitate to culture media and inhibition of mitochondrial FA oxidation sensitized C4-2B cells to palmitate-induced apoptosis. Whereas in PC-3 cells, palmitate induced apoptosis, which was prevented by pretreatment of PC-3 cells with FAs, and this protective effect required DGAT-1-mediated triacylglycerol synthesis. These outcomes highlight for the first-time heterogeneity of lipid metabolism in prostate cancer cells and the potential influence that obesity-associated dyslipidemia or host circulating has on prostate cancer progression. IMPLICATIONS: Extracellular-derived FAs are primary building blocks for complex lipids and heterogeneity in FA metabolism exists in prostate cancer that can influence tumor cell behavior.
前列腺癌细胞表现出改变的细胞代谢，但值得注意的是，它们没有出现沃伯格代谢的特征。前列腺癌细胞表现出脂肪酸（FA）合成的增加；然而，关于细胞外 FAs，例如循环中的那些，如何可能支持前列腺癌的进展，知之甚少。在这里，我们表明，增加 FA 的可用性会增加培养的患者衍生肿瘤外植体、LNCaP 和 C4-2B 球体、一系列前列腺癌细胞（LNCaP、C4-2B、22Rv1、PC-3）和前列腺上皮细胞（PNT1）的细胞内三酰基甘油含量。与葡萄糖（约 13%）和谷氨酰胺（约 4%）相比，细胞外 FAs 是所有细胞系中总脂质库的主要碳源（约 83%），并且与 PNT1 细胞相比，前列腺癌细胞的 FA 氧化率更高，PNT1 细胞优先将细胞外 FAs 分配到三酰基甘油中。由于 C4-2B 细胞中 FA 氧化的速率较高，当向培养基中添加棕榈酸并抑制线粒体 FA 氧化时，细胞仍能保持存活，而 C4-2B 细胞对棕榈酸诱导的细胞凋亡变得敏感。然而，在 PC-3 细胞中，棕榈酸诱导细胞凋亡，而用 FAs 预处理 PC-3 细胞可防止这种细胞凋亡，并且这种保护作用需要 DGAT-1 介导的三酰基甘油合成。这些结果首次强调了前列腺癌细胞中脂质代谢的异质性，以及肥胖相关的血脂异常或宿主循环对前列腺癌进展的潜在影响。意义：细胞外来源的 FAs 是复杂脂质的主要结构单元，并且在前列腺癌中存在 FA 代谢的异质性，这可能会影响肿瘤细胞的行为。
