Extracellular Fatty Acids Are the Major Contributor to Lipid Synthesis in Prostate Cancer
Extracellular Fatty Acids Are the Major Contributor to Lipid Synthesis in Prostate Cancer
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DOI：
10.1158/1541-7786.mcr-18-0347
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发表时间：
2019-04-01
影响因子：
5.2
通讯作者：
Hoy, Andrew J.
中科院分区：
文献类型：
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作者：
Balaban, Seher;Nassar, Zeyad D.;Hoy, Andrew J.
前列腺癌细胞表现出细胞新陈代谢的改变，但值得注意的是，没有华宝新陈代谢的特征。前列腺癌细胞表现出脂肪酸(FA)的从头合成增加；然而，人们对细胞外FA(如循环中的FA)如何支持前列腺癌进展知之甚少。在这里，我们发现，增加FA的利用率增加了培养的患者来源的肿瘤外植体、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)中三酰甘油的含量。与葡萄糖(13%)和谷氨酰胺(4%)相比，在所有细胞系中，胞外FAs是碳的主要来源(类似于83%)，与葡萄糖(类似于13%)和谷氨酰胺(类似于4%)相比，前列腺癌细胞的FA氧化率比PNT1细胞更大，PNT1细胞优先将胞外FAs分割为三酰甘油。由于C4-2B细胞中FA的氧化率较高，因此在向培养液中添加棕榈酸酯和抑制线粒体FA氧化的情况下，C4-2B细胞仍能存活。而在PC-3细胞中，棕榈酸酯可诱导PC-3细胞的凋亡，这种作用可被FAs预先阻止，而这种保护作用需要DGAT-1介导的三酰甘油的合成。这些结果首次强调了前列腺癌细胞中脂代谢的异质性，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：细胞外衍生的FA是复杂脂质的主要构建块，前列腺癌中FA代谢的异质性可以影响肿瘤细胞的行为。
Prostate cancer cells exhibit altered cellular metabolism but, notably, not the hallmarks of Warburg metabolism. Prostate cancer cells exhibit increased de novo 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 (similar to 83%) of carbons to the total lipid pool in all cell lines, compared with glucose (similar to 13%) and glutamine (similar to 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.