Glucose metabolism and cell death in cancer

白血病细胞在肿瘤进展中克服的一个关键障碍是对细胞因子生长的依赖 生存的因素。我们已经证明，在承诺细胞死亡之前，生长因子剥夺 正常淋巴样细胞导致细胞萎缩，糖代谢降低，活化 抗凋亡的Bcl2家族成员MCL1的自噬和蛋白降解。相比之下， 白血病细胞或具有激活形式的致癌激酶Akt/PKB的细胞可以抵抗萎缩和细胞死亡， 是高度糖酵解的，即使在没有生长因子的情况下也能保持MCL1。这方面的作用增加了 葡萄糖代谢尚不清楚。我们发现，癌症的特点是葡萄糖代谢增加 激活抗细胞凋亡的营养信号通路。这种葡萄糖刺激的信号通路包括 抑制糖原合成酶激酶-3Ff的磷酸化？(GSK3)通过蛋白激酶C(PKC)，这是 防止MCL1降级。MCM的稳定似乎至关重要，因为增强的葡萄糖代谢未能 在MEL-1缺陷细胞中提供生存优势。葡萄糖水解促进蛋白激酶C的途径 MCM的活性和调控仍然不确定。致癌的Akt也需要葡萄糖代谢 在缺乏生长因子和磷酸戊糖途径(PPP)的情况下防止细胞死亡，特别是， 可能很重要。相反，我们发现，Bcl-XL支持小鼠的生长因子非依赖性生存。 缺乏葡萄糖，而必须依靠自噬来维持线粒体代谢产物和 减轻细胞死亡。我们假设癌细胞对葡萄糖的利用增加会启动细胞 影响线粒体和其他细胞死亡途径的代谢和生存途径 可能在癌细胞抵抗死亡中发挥重要作用。我们建议：(1)确定 抗凋亡葡萄糖介导的信号转导激活PKC和稳定MCM；(2)检测其作用 确定PPP或替代物对细胞糖代谢表达致癌Akt的作用 代谢途径在MCL1和细胞死亡的调节中发挥作用；以及(3)确定葡萄糖增加的作用 自噬作为细胞代谢和细胞因子撤除中存活的来源的代谢。这些研究 将确定细胞代谢调节细胞死亡的机制，以及高度糖酵解如何 癌细胞的性质可能会影响这些途径，以更好地了解癌细胞的生存 机械装置。

A key barrier that leukemic cells overcome in cancer progression is dependence on cytokine growth factors for survival. We have shown that prior to commitment to cell death, growth factor-deprivation of normal lymphoid cells results in cellular atrophy with decreased glucose metabolism, activation of autophagy, and proteolytic degradation of the anti-apoptotic Bcl-2 family member, Mcl1. In contrast, leukemic cells or cells with activated forms of the oncogenic kinase, Akt/PKB, resist atrophy and cell death, are highly glycolytic, and maintain Mcl1 even in the absence of growth factors. The role of this increased glucose metabolism is unknown. We show that increased glucose metabolism characteristic of cancer activates an anti-apoptotic nutrient signaling pathway. This glucose-stimulated signaling pathway involves inhibitory phosphorylation of glycogen synthase kinase-3ff//? (GSK3) by protein kinase C (PKC), which prevents degradation of Mcl1. McM stabilization appears critical as enhanced glucose metabolism failed to provide a survival advantage in Mel 1-deficient cells. The means by which glucose hydrolysis promotes PKC activity and regulates of McM remain uncertain. Glucose metabolism is also required for oncogenic Akt to prevent cell death in the absence of growth factor and the pentose phosphate pathway (PPP), in particular, may be important. In contrast, we show that Bcl-xL supports growth factor-independent survival in the absence of glucose and instead must rely on autophagy to both maintain mitochondrial metabolites and attenuate cell death. We hypothesize that the increased glucose utilization of cancer cells initiates cell metabolism and survival pathways that impact both mitochondrial and alternative cell death pathways and may play important roles in cancer cell resistance to death. We propose to: (1) Identify the mechanism of anti-apoptotic glucose-mediated signal transduction to activate PKC and stabilize McM; (2) Examine the role of glucose metabolism in cells expressing oncogenic Akt to determine the role that the PPP or alternative metabolic pathways play in regulation of Mcl1 and cell death; and (3) Establish the role of increased glucose metabolism on autophagy as a source of cell metabolism and survival in cytokine withdrawal. These studies will identify mechanisms by which cell metabolism may regulate cell death and how the highly glycolytic nature of cancer cells may affect these pathways to better understand cancer cell survival mechanisms.