Upregulation of cytosolic phosphoenolpyruvate carboxykinase is a critical metabolic event in melanoma cells that repopulate tumors.
Upregulation of cytosolic phosphoenolpyruvate carboxykinase is a critical metabolic event in melanoma cells that repopulate tumors.
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胞质磷酸烯醇丙酮酸羧激酶的上调是肿瘤再生的黑色素瘤细胞中的一个关键代谢事件
DOI：
10.1158/0008-5472.can-14-2615
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发表时间：
2015-04-01
期刊：
影响因子：
11.2
通讯作者：
Huang B
中科院分区：
文献类型：
--
作者：
Li Y;Luo S;Ma R;Liu J;Xu P;Zhang H;Tang K;Ma J;Zhang Y;Liang X;Sun Y;Ji T;Wang N;Huang B
虽然代谢缺陷已经在分化的肿瘤细胞中得到了广泛的研究，但很少有人关注再生肿瘤的干细胞样细胞（tumor-repopulating cells [TRC]）的代谢特性。在这里，我们发现在3D软纤维蛋白凝胶中培养的黑色素瘤TRCs通过劫持细胞内酶磷酸烯醇丙酮酸羧激酶（PCK1）来重编程葡萄糖代谢，PCK1是糖异生的关键参与者。令人惊讶的是，TRCs中PCK1的上调并不介导糖异生，而是促进葡萄糖侧分支代谢，包括丝氨酸和甘油-3-磷酸途径。此外，这种逆行的葡萄糖碳流加强而不是拮抗糖酵解和葡萄糖消耗。在体外，沉默PCK1或抑制其酶活性会减缓TRCs的生长，并阻碍体内肿瘤的发生。总的来说，我们的工作揭示了黑色素瘤中肿瘤再生细胞的代谢特征，这对靶向这种疾病的一个独特方面具有重要意义。
While metabolic defects have been investigated extensively in differentiated tumor cells, much less attention has been directed to the metabolic properties of stem-like cells that repopulate tumors (tumor-repopulating cells [TRC]). Here we show that melanoma TRCs cultured in 3D soft fibrin gels reprogram glucose metabolism by hijacking the cytosolic enzyme phosphoenolpyruvate carboxykinase (PCK1), a key player in gluconeogenesis. Surprisingly, upregulated PCK1 in TRCs did not mediate gluconeogenesis but promoted glucose side-branch metabolism, including in the serine and glycerol-3-phosphate pathways. Moreover, this retrograde glucose carbon flow strengthened rather than antagonized glycolysis and glucose consumption. Silencing PCK1 or inhibiting its enzymatic activity slowed the growth of TRCs in vitro and impeded tumorigenesis in vivo. Overall, our work unveiled metabolic features of tumor-repopulating cells in melanoma that have implications for targeting a unique aspect of this disease.