Glucose metabolism and cell death in cancer

癌症中的葡萄糖代谢和细胞死亡

• 批准号: 7259909
• 负责人: Jeffrey C. Rathmell
• 金额: $ 29.62万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7259909
• 关键词: Affect; Apoptosis; Apoptotic; Atrophic; Attenuated; Autophagocytosis; B-Lymphocytes; Bax protein; Cell Death; Cell Line; Cell Survival; Cells; Cessation of life; Characteristics; Dependence; Dependency; Digestion; Disruption; Down-Regulation; Family; Family member; Glucose; Glucose Transporter; Glycogen Synthase Kinases; Growth Factor; Hematopoietic; Hydrolysis; Leukemic Cell; Lymphoid; Lymphoid Cell; Malignant Neoplasms; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Myelogenous; Nature; Neoplasms; Nutrient; Oncogenic; Pathway interactions; Pentosephosphate Pathway; Phosphorylation; Phosphotransferases; Play; Process; Protein Family; Protein Isoforms; Protein Kinase C; Proteins; Rate; Regulation; Research Personnel; Resistance; Role; Signal Pathway; Signal Transduction; Source; Supporting Cell; Testing; Withdrawal; base; cancer cell; cytokine; deprivation; glucose metabolism; hexokinase; inorganic phosphate; member; mitochondrial autophagy; novel; prevent; programs; tumor progression

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.

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生存依赖于细胞因子生长因子。我们已经表明，在细胞死亡之前，正常淋巴细胞的生长因子剥夺导致细胞萎缩，葡萄糖代谢降低，自噬激活，抗凋亡Bcl-2家族成员Mcl 1蛋白水解降解。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，癌症的葡萄糖代谢特征增加激活了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/3（GSK 3）的抑制性磷酸化，从而阻止Mcl 1的降解。Mcl 1稳定似乎至关重要，因为增强葡萄糖代谢未能在Mcl 1缺陷细胞中提供存活优势。葡萄糖水解促进PKC活性和调节Mcl 1的方式仍不确定。葡萄糖代谢也是致癌Akt在缺乏生长因子的情况下防止细胞死亡所必需的，特别是磷酸戊糖途径（PPP）可能很重要。相反，我们发现Bcl-xL在没有葡萄糖的情况下支持生长因子非依赖性存活，而是必须依赖自噬来维持线粒体代谢产物和减弱细胞死亡。我们推测，癌细胞葡萄糖利用的增加启动了细胞代谢和存活途径，这些途径影响线粒体和替代细胞死亡途径，并可能在癌细胞抵抗死亡中发挥重要作用。我们建议：（1）确定抗凋亡葡萄糖介导的信号转导机制，以激活PKC并稳定Mcl 1：（2）检测葡萄糖代谢在表达致癌Akt的细胞中的作用，以确定PPP或替代代谢途径在调节Mcl 1和细胞死亡中的作用;和（3）确定葡萄糖代谢增加对自噬的作用，作为细胞代谢和细胞因子去除中的存活的来源。这些研究将确定细胞代谢可能调节细胞死亡的机制，以及癌细胞的高度糖酵解性质如何影响这些途径，以更好地了解癌细胞存活机制。