Hypoxia and the metabolic phenotype of prostate cancer cells
Hypoxia and the metabolic phenotype of prostate cancer cells
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DOI：
10.1016/j.bbabio.2009.06.003
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发表时间：
2009-12-01
影响因子：
4.3
通讯作者：
Moyes, C. D.
中科院分区：
文献类型：
--
作者：
Higgins, L. H.;Withers, H. G.;Moyes, C. D.
许多癌细胞在缺氧条件下具有不寻常的生长能力，但这种代谢表型的起源尚不清楚。我们比较了三种常见的前列腺癌细胞模型（LNCaP、DU145、PO）的代谢表型，评估了能量代谢、代谢基因表达以及对各种培养环境（体外和异种移植）的反应。基于呼吸、乳酸生成、[ATP]、代谢基因表达以及这些参数对缺氧的敏感性，LNCaP细胞比PO和DU145细胞具有更强的氧化表型。PC3和DU145细胞具有相似的复合物II和mtDNA水平，但复合物III和IV活性较低，并且对二硝酸盐或二氯乙酸无反应，表明它们的糖酵解表型是由于线粒体功能障碍而不是调节。常氧下的高传代将LNCaP从氧化细胞转化为糖酵解细胞（基于呼吸和乳酸生成），并改变了代谢基因的表达。尽管lncap衍生的细胞在线粒体酶活性方面与亲本系不同，但在线粒体含量（以心磷脂水平评估）方面没有差异。当lncap来源的细胞作为异种移植物在免疫缺陷小鼠中生长时，存在缺氧反应的要素（例如，VEGF mRNA升高），但特定系的糖酵解、线粒体和脂肪酸代谢基因的表达发生了变化。体外低氧不影响SREBP轴的mRNA水平，也没有显著改变任何细胞系甘油三酯的产生，这表明缺氧条件不会直接上调重新生成脂肪酸的途径。总的来说，这些研究证明了这些前列腺癌模型在代谢方面的重要差异。这种代谢差异将对涉及代谢靶点的治疗策略产生重要影响。(C) 2009 Elsevier B.V.版权所有
Many cancer cells have an unusual ability to grow in hypoxia, but the origins of this metabolic phenotype remain unclear. We compared the metabolic phenotypes of three common prostate cancer cell models (LNCaP, DU145, PO), assessing energy metabolism, metabolic gene expression, and the response to various culture contexts (in vitro and xenografts). LNCaP cells had a more oxidative phenotype than PO and DU145 cells based upon respiration, lactate production, [ATP], metabolic gene expression, and sensitivity of these parameters to hypoxia. PC3 and DU145 cells possessed similar Complex II and mtDNA levels, but lower Complex III and IV activities, and were unresponsive to dinitrophenol or dichloroacetate, suggesting that their glycolytic phenotype is due to mitochondrial dysfunction rather than regulation. High passage under normoxia converted LNCaP from oxidative to glycolytic cells (based on respiration and lactate production), and altered metabolic gene expression. Though LNCaP-derived cells differed from the parental line in mitochondrial enzyme activities, none differed in mitochondrial content (assessed as cardiolipin levels). When LNCaP-derived cells were grown as xenografts in immunodeficient mice, there were elements of a hypoxic response (e.g., elevated VEGF mRNA) but line-specific changes in expression of select glycolytic, mitochondrial and fatty acid metabolic genes. Low oxygen in vitro did not influence the mRNA levels of SREBP axis, nor did it significantly alter triglyceride production in any of the cell lines suggesting that the pathway of de novo fatty acid synthesis is not directly upregulated by hypoxic conditions. Collectively, these studies demonstrate important differences in the metabolism of these prostate cancer models. Such metabolic differences would have important ramifications for therapeutic strategies involving metabolic targets. (C) 2009 Elsevier B.V. All rights reserved.