Molecular causes of the aberrant choline phospholipid metabolism in breast cancer
Molecular causes of the aberrant choline phospholipid metabolism in breast cancer
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DOI：
10.1158/0008-5472.can-03-3829
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发表时间：
2004-06-15
期刊：
影响因子：
11.2
通讯作者：
Bhujwalla, ZM
中科院分区：
文献类型：
--
作者：
Glunde, K;Jie, C;Bhujwalla, ZM
质子磁共振波谱(H-1MRS)始终检测到乳腺良恶性病变中胆碱磷脂代谢产物的显著差异。了解这些代谢差异背后的分子原因至关重要，因为这可能确定癌细胞攻击的新靶点。本研究用H-1和C-13磁共振波谱研究了[1，2-C-13]胆碱标记的乳腺癌细胞和正常人乳腺上皮细胞胆碱膜代谢的差异。通过长时间和短时间将细胞暴露在[1，2-C-13]胆碱中以区分胆碱代谢的分解代谢途径和合成代谢途径，评估了细胞膜和含胆碱代谢物的水溶池之间的代谢通量。使用微阵列进行基因表达分析，以了解这些变化背后的分子机制。与正常HMEC相比，乳腺癌细胞的磷胆碱(PC；P<；0.001)、总胆碱代谢产物(P<；0.01)显著增加，甘油磷胆碱(P<；0.05)显著降低。与内皮细胞相比，乳腺癌细胞的胆碱(P<；0.001)和磷胆碱(P<；0.001)的C-13-浓集减少，表明乳腺癌细胞从膜磷脂酰胆碱到胆碱和磷胆碱的代谢通量较高。与HMEC相比，乳腺癌细胞中胆碱激酶和磷脂酶C显著高表达，溶血磷脂酶1、磷脂酶A2和磷脂酶D显著低表达。磁共振波谱数据表明，乳腺癌细胞中磷胆碱的升高主要是由于胆碱激酶活性的增加和磷脂酶C活性的增加所介导的分解代谢的增加。这些观察结果与芯片分析中检测到的胆碱激酶和磷脂酶C的过度表达是一致的。
Proton magnetic resonance spectroscopy (H-1 MRS) consistently detects significant differences in choline phospholipid metabolites of malignant versus benign breast lesions. It is critically important to understand the molecular causes underlying these metabolic differences, because this may identify novel targets for attack in cancer cells. In this study, differences in choline membrane metabolism were characterized in breast cancer cells and normal human mammary epithelial cells (HMECs) labeled with [1,2-C-13]choline, using H-1 and C-13 magnetic resonance spectroscopy. Metabolic fluxes between membrane and water-soluble pool of choline-containing metabolites were assessed by exposing cells to [1,2-C-13]choline for long and short periods of time to distinguish between catabolic and anabolic pathways in choline metabolism. Gene expression analysis using microarrays was performed to understand the molecular mechanisms underlying these changes. Breast cancer cells exhibited increased phosphocholine (PC; P < 0.001), total choline-containing metabolites (P < 0.01), and significantly decreased glycerophosphocholine (P < 0.05) compared with normal HMECs. Decreased C-13-enrichment was detected in choline (P < 0.001) and phosphocholine (P < 0.05, P < 0.001) of breast cancer cells compared with HMECs, indicating a higher metabolic flux from membrane phosphatidylcholine to choline and phosphocholine in breast cancer cells. Choline kinase and phospholipase C were significantly overexpressed, and lysophospholipase 1, phospholipase A2, and phospholipase D were significantly underexpressed, in breast cancer cells compared with HMECs. The magnetic resonance spectroscopy data indicated that elevated phosphocholine in breast cancer cells was primarily attributable to increased choline kinase activity and increased catabolism mediated by increased phospholipase C activity. These observations were consistent with the overexpression of choline kinase and phospholipase C detected in the microarray analyses.