Ras transformation requires metabolic control by 6-phosphofructo-2-kinase
Ras transformation requires metabolic control by 6-phosphofructo-2-kinase
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DOI：
10.1038/sj.onc.1209709
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发表时间：
2006-11-01
期刊：
影响因子：
8
通讯作者：
Chesney, J.
中科院分区：
文献类型：
--
作者：
Telang, S.;Yalcin, A.;Chesney, J.
肿瘤细胞运输大量的葡萄糖，以便在肿瘤的不适宜环境中产生合成代谢前体和能量。ras信号通路在几种癌症中被激活，并且已经发现刺激糖酵解流到乳酸。糖酵解由ras通过6-磷酸果糖-2-激酶/果糖-2，6-二磷酸酶（PFK 2/FBPase）的活性调节，PFK 2/FBPase调节细胞内别构糖酵解激活剂果糖-2，6-二磷酸（F2，6 BP）的浓度。我们在此报告，小鼠成纤维细胞或人支气管上皮细胞的连续永生化和ras转化矛盾地降低了F2，6 BP的细胞内浓度。F2，6 BP的细胞内浓度的这种显著降低使转化细胞对PFK 2/FBPase抑制的抗代谢作用敏感。此外，尽管共表达所有四种mRNA种类（PFKFB 1 -4），但ras转化的小鼠肺成纤维细胞中诱导型PFKFB 3基因的杂合基因组缺失抑制F2，6 BP产生，糖酵解通量为乳酸盐，并在无胸腺小鼠中生长为软琼脂集落或肿瘤。这些数据表明，PFKFB 3蛋白产物可能作为一个重要的下游代谢介质的致癌ras，我们建议，这种酶的药理学抑制应选择性地抑制高速率的糖酵解和癌细胞的生长。
Neoplastic cells transport large amounts of glucose in order to produce anabolic precursors and energy within the inhospitable environment of a tumor. The ras signaling pathway is activated in several cancers and has been found to stimulate glycolytic flux to lactate. Glycolysis is regulated by ras via the activity of 6-phosphofructo-2-kinase/fructose- 2,6-bisphosphatases (PFK2/FBPase), which modulate the intracellular concentration of the allosteric glycolytic activator, fructose-2,6-bisphosphate (F2,6BP). We report herein that sequential immortalization and ras-transformation of mouse fibroblasts or human bronchial epithelial cells paradoxically decreases the intracellular concentration of F2,6BP. This marked reduction in the intracellular concentration of F2,6BP sensitizes transformed cells to the antimetabolic effects of PFK2/FBPase inhibition. Moreover, despite co-expression of all four mRNA species (PFKFB1-4), heterozygotic genomic deletion of the inducible PFKFB3 gene in ras-transformed mouse lung fibroblasts suppresses F2,6BP production, glycolytic flux to lactate, and growth as soft agar colonies or tumors in athymic mice. These data indicate that the PFKFB3 protein product may serve as an essential downstream metabolic mediator of oncogenic ras, and we propose that pharmacologic inhibition of this enzyme should selectively suppress the high rate of glycolysis and growth by cancer cells.