Glucose transporter 1-mediated glucose uptake is limiting for B-cell acute lymphoblastic leukemia anabolic metabolism and resistance to apoptosis.
Glucose transporter 1-mediated glucose uptake is limiting for B-cell acute lymphoblastic leukemia anabolic metabolism and resistance to apoptosis.
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DOI：
10.1038/cddis.2014.431
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发表时间：
2014-10-16
影响因子：
9
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癌细胞的代谢谱长期以来一直被认为是改变的，并提供了新的治疗机会。特别是，广泛的实体和液体肿瘤都使用有氧糖酵解来提供能量和支持细胞生长。这一代谢程序通过糖酵解导致高速率的葡萄糖消耗，即使在氧气存在的情况下也会分泌乳酸。确定有氧糖酵解中的限制事件和癌细胞对代谢抑制的反应现在对于利用这种潜在的代谢依赖性至关重要。在这里，我们研究了葡萄糖摄取和葡萄糖转运蛋白Glut 1在BCR-Abl+ B细胞急性淋巴细胞白血病细胞（B-ALL）的代谢和代谢应激反应中的作用。B-ALL细胞高度糖酵解，原代人B-ALL样本依赖于糖酵解。我们发现B-ALL细胞表达多种葡萄糖转运蛋白，Glut 1的条件性基因缺失导致葡萄糖摄取的部分丧失。然而，这种降低的葡萄糖转运能力足以对B-ALL细胞进行代谢重编程，以减少合成代谢并增加分解代谢通量。细胞增殖减少，也观察到有限程度的凋亡。重要的是，Glut 1缺陷型B-ALL细胞不能在体内积累，并且Glut 1缺失抑制了白血病进展。类似地，用中等剂量的2-脱氧葡萄糖（2-DG）对有氧糖酵解的药理学抑制减缓了B-ALL细胞增殖，但仅在高剂量时发生广泛的凋亡。然而，2-DG诱导促凋亡蛋白Bim和致敏的B-ALL细胞的酪氨酸激酶抑制剂达沙替尼在体内。总之，这些数据表明，尽管表达多种葡萄糖转运蛋白，B-ALL细胞依赖于Glut 1来维持有氧糖酵解和合成代谢。此外，葡萄糖代谢的部分抑制足以使癌细胞对特异性靶向治疗敏感，表明抑制有氧糖酵解作为B-ALL治疗的合理辅助方法。
The metabolic profiles of cancer cells have long been acknowledged to be altered and to provide new therapeutic opportunities. In particular, a wide range of both solid and liquid tumors use aerobic glycolysis to supply energy and support cell growth. This metabolic program leads to high rates of glucose consumption through glycolysis with secretion of lactate even in the presence of oxygen. Identifying the limiting events in aerobic glycolysis and the response of cancer cells to metabolic inhibition is now essential to exploit this potential metabolic dependency. Here, we examine the role of glucose uptake and the glucose transporter Glut1 in the metabolism and metabolic stress response of BCR-Abl+ B-cell acute lymphoblastic leukemia cells (B-ALL). B-ALL cells were highly glycolytic and primary human B-ALL samples were dependent on glycolysis. We show B-ALL cells express multiple glucose transporters and conditional genetic deletion of Glut1 led to a partial loss of glucose uptake. This reduced glucose transport capacity, however, was sufficient to metabolically reprogram B-ALL cells to decrease anabolic and increase catabolic flux. Cell proliferation decreased and a limited degree of apoptosis was also observed. Importantly, Glut1-deficient B-ALL cells failed to accumulate in vivo and leukemic progression was suppressed by Glut1 deletion. Similarly, pharmacologic inhibition of aerobic glycolysis with moderate doses of 2-deoxyglucose (2-DG) slowed B-ALL cell proliferation, but extensive apoptosis only occurred at high doses. Nevertheless, 2-DG induced the pro-apoptotic protein Bim and sensitized B-ALL cells to the tyrosine kinase inhibitor Dasatinib in vivo. Together, these data show that despite expression of multiple glucose transporters, B-ALL cells are reliant on Glut1 to maintain aerobic glycolysis and anabolic metabolism. Further, partial inhibition of glucose metabolism is sufficient to sensitize cancer cells to specifically targeted therapies, suggesting inhibition of aerobic glycolysis as a plausible adjuvant approach for B-ALL therapies.
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影响因子：
29
作者：
Macintyre AN;Gerriets VA;Nichols AG;Michalek RD;Rudolph MC;Deoliveira D;Anderson SM;Abel ED;Chen BJ;Hale LP;Rathmell JC
通讯作者：
Rathmell JC
影响因子：
20.3
作者：
Everts, Bart;Amiel, Eyal;Pearce, Edward J.
通讯作者：
Pearce, Edward J.
影响因子：
3.7
作者：
Hresko RC;Hruz PW
通讯作者：
Hruz PW
影响因子：
64.5
作者：
Israelsen WJ;Dayton TL;Davidson SM;Fiske BP;Hosios AM;Bellinger G;Li J;Yu Y;Sasaki M;Horner JW;Burga LN;Xie J;Jurczak MJ;DePinho RA;Clish CB;Jacks T;Kibbey RG;Wulf GM;Di Vizio D;Mills GB;Cantley LC;Vander Heiden MG
通讯作者：
Vander Heiden MG
影响因子：
16
作者：
Jones, RG;Plas, DR;Thompson, CB
通讯作者：
Thompson, CB