Glucose metabolism and cell death in cancer

描述(由申请人提供)：白血病细胞在癌症进展中克服的一个关键障碍是依赖细胞因子生长因子生存。我们已经证明，在承诺细胞死亡之前，剥夺正常淋巴样细胞的生长因子会导致细胞萎缩，葡萄糖代谢降低，自噬激活，抗凋亡的Bcl-2家族成员MCL1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，高度糖酵解，即使在没有生长因子的情况下也能保持MCL1。这种葡萄糖代谢增加的作用尚不清楚。我们发现，癌症的葡萄糖代谢增加的特性激活了一条抗细胞凋亡的营养信号通路。这种葡萄糖刺激的信号通路涉及蛋白激酶C(PKC)对糖原合成酶激酶-3a/β(GSK3)的抑制磷酸化，从而阻止MCL1的降解。MCL1的稳定性似乎至关重要，因为增强的葡萄糖代谢不能在MCL1缺陷的细胞中提供生存优势。葡萄糖水解促进PKC活性和调节MCL1的途径仍不清楚。在缺乏生长因子的情况下，致癌Akt也需要葡萄糖代谢来防止细胞死亡，尤其是磷酸戊糖途径(PPP)可能是重要的。相反，我们发现，在没有葡萄糖的情况下，Bcl-XL支持生长因子非依赖性存活，而必须依赖自噬来维持线粒体代谢物和减轻细胞死亡。我们推测，癌细胞对葡萄糖的利用增加启动了细胞代谢和生存途径，影响了线粒体和其他细胞死亡途径，并可能在癌细胞抵抗死亡中发挥重要作用。我们建议：(1)确定葡萄糖介导的抗凋亡信号转导激活PKC和稳定MCL1的机制；(2)检测表达癌基因Akt的细胞中葡萄糖代谢的作用，以确定PPP或其他代谢途径在调节MCL1和细胞死亡中所起的作用；以及(3)建立葡萄糖代谢增加对自噬的作用，作为细胞代谢和细胞因子退出的来源。这些研究将确定细胞代谢可能调节细胞死亡的机制，以及癌细胞的高度糖酵解性质可能如何影响这些途径，以更好地了解癌细胞的生存机制。

DESCRIPTION (provided by applicant): 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-3a/¿ (GSK3) by protein kinase C (PKC), which prevents degradation of Mcl1. Mcl1 stabilization appears critical as enhanced glucose metabolism failed to provide a survival advantage in Mcl1-deficient cells. The means by which glucose hydrolysis promotes PKC activity and regulates of Mcl1 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 Mcl1; (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.