Glucose metabolism and cell death in cancer

白血病细胞在癌症进展中克服的一个关键障碍是依赖于细胞因子生长 生存的因素。我们已经证明，在细胞死亡之前，生长因子剥夺， 正常淋巴样细胞导致细胞萎缩，葡萄糖代谢降低， 自噬和抗凋亡Bcl-2家族成员Mcl 1的蛋白水解降解。与此相反， 白血病细胞或具有致癌激酶Akt/PKB活化形式的细胞抵抗萎缩和细胞死亡， 是高度糖酵解的，并且即使在没有生长因子的情况下也维持Mcl 1。这一作用增强了 葡萄糖代谢未知。我们发现癌症的葡萄糖代谢增加 激活抗凋亡营养信号通路。这种葡萄糖刺激的信号通路涉及 抑制糖原合成酶激酶-3ff//？蛋白激酶C（PKC）， 防止Mcl 1的降解。由于葡萄糖代谢的增强未能 在Mel 1缺陷细胞中提供存活优势。葡萄糖水解促进PKC的途径 MCM的活性和调控机制尚不明确。葡萄糖代谢也是致癌Akt所必需的， 在缺乏生长因子和戊糖磷酸途径（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支持非生长因子依赖性生存。 缺乏葡萄糖，而是必须依赖自噬来维持线粒体代谢物， 减少细胞死亡。我们假设癌细胞对葡萄糖的利用增加， 影响线粒体和替代细胞死亡途径的代谢和存活途径， 可能在癌细胞抵抗死亡中起重要作用。我们建议：（1）确定 抗凋亡葡萄糖介导的信号转导，以激活PKC和稳定McM;（2）检查作用 表达致癌Akt的细胞中葡萄糖代谢的变化，以确定PPP或替代物 代谢途径在调节Mcl 1和细胞死亡中起作用;（3）建立葡萄糖增加的作用 在细胞因子撤出中，自噬作为细胞代谢和存活的来源。这些研究 将确定细胞代谢可能调节细胞死亡的机制，以及高度糖酵解的 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 机制等

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.