Metabolomic profile of glycolysis and the pentose phosphate pathway identifies the central role of glucose-6-phosphate dehydrogenase in clear cell-renal cell carcinoma.
Metabolomic profile of glycolysis and the pentose phosphate pathway identifies the central role of glucose-6-phosphate dehydrogenase in clear cell-renal cell carcinoma.
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DOI：
10.18632/oncotarget.3823
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发表时间：
2015-05-30
期刊：
影响因子：
--
通讯作者：
Ditonno P
中科院分区：
文献类型：
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作者：
Lucarelli G;Galleggiante V;Rutigliano M;Sanguedolce F;Cagiano S;Bufo P;Lastilla G;Maiorano E;Ribatti D;Giglio A;Serino G;Vavallo A;Bettocchi C;Selvaggi FP;Battaglia M;Ditonno P
对癌症代谢组的分析表明，增殖的肿瘤细胞需要大量不同的营养物质，以支持其高增殖率。在这项研究中，我们分析了人类透明细胞-肾细胞癌（ccRCC）中糖酵解和磷酸戊糖途径（PPP）的代谢特征，并评估了这些途径在维持细胞增殖、维持NADPH水平和产生活性氧（ROS）中的作用。代谢组学分析显示ccRCC肿瘤样品中葡萄糖摄取和利用增加的明确特征。葡萄糖-6-磷酸脱氢酶（G6 PDH）水平升高与PPP衍生代谢产物水平升高相关，表明该途径在RCC相关代谢改变中发挥重要作用。G6 PDH抑制导致癌细胞存活率显著降低、NADPH水平降低和ROS产生增加，表明PPP在调控ccRCC氧化还原稳态中起重要作用。与糖酵解酶水平低的受试者相比，糖酵解酶水平高的患者的无进展生存率和癌症特异性生存率降低。我们的数据表明，致癌信号通路可能通过改变糖代谢来促进ccRCC。阻断通过该途径的通量可以作为新的治疗靶点。
The analysis of cancer metabolome has shown that proliferating tumor cells require a large quantities of different nutrients in order to support their high rate of proliferation. In this study we analyzed the metabolic profile of glycolysis and the pentose phosphate pathway (PPP) in human clear cell-renal cell carcinoma (ccRCC) and evaluate the role of these pathways in sustaining cell proliferation, maintenance of NADPH levels, and production of reactive oxygen species (ROS). Metabolomic analysis showed a clear signature of increased glucose uptake and utilization in ccRCC tumor samples. Elevated levels of glucose-6-phosphate dehydrogenase (G6PDH) in association with higher levels of PPP-derived metabolites, suggested a prominent role of this pathway in RCC-associated metabolic alterations. G6PDH inhibition, caused a significant decrease in cancer cell survival, a decrease in NADPH levels, and an increased production of ROS, suggesting that the PPP plays an important role in the regulation of ccRCC redox homeostasis. Patients with high levels of glycolytic enzymes had reduced progression-free and cancer-specific survivals as compared to subjects with low levels. Our data suggest that oncogenic signaling pathways may promote ccRCC through rerouting the sugar metabolism. Blocking the flux through this pathway may serve as a novel therapeutic target.