Elucidating the Mechanisms by which Hexokinase 2 Regulates Breast Cancer Metastasis

阐明己糖激酶 2 调节乳腺癌转移的机制

• 批准号: 9751623
• 负责人: Catherine Blaha
• 金额: $ 5万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-08-16 至 2022-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9751623
• 关键词: Adult; Affect; Affinity; Anabolism; Antibodies; Antioxidants; Applications Grants; Attenuated; Body part; Breast Cancer Cell; Breast Cancer therapy; Breast cancer metastasis; Cancer Model; Cell Line; Cell physiology; Cells; Data; Deoxyglucose; Development; Distant; Embryo; Epithelial; Exhibits; Generations; Glucose; Glucose-6-Phosphate; Glutathione; Glycogen Synthase Kinase 3; Glycolysis; Hexokinase 2; Hexosamines; Implant; In Vitro; Incidence; Link; Lung; Malignant Neoplasms; Mammalian Cell; Mammary Neoplasms; Mammary gland; Mediating; Mesenchymal; Metabolic; Metastatic breast cancer; Mitochondria; Modification; Mouse Cell Line; Mouse Mammary Tumor Virus; Mus; NADP; Neoplasm Metastasis; Nonmetastatic; Normal Cell; Organ; Oxidative Stress; Oxygen; Palpable; Pathway interactions; Patients; Pentosephosphate Pathway; Phenotype; Phosphorylation; Physiological; Play; Positron-Emission Tomography; Primary Neoplasm; Process; Production; Property; Protein Isoforms; Proteins; Reactive Oxygen Species; Reduced Glutathione; Regulation; Research; Ribonucleotides; Role; Stress; Survival Rate; Tissues; Tumor Cell Line; Tumorigenicity; Up-Regulation; Warburg Effect; base; cancer cell; cancer imaging; chemotherapy; combat; glucose analog; glucose metabolism; glucose uptake; hexokinase; in vivo; knock-down; malignant breast neoplasm; migration; mortality; mouse model; novel; novel therapeutics; overexpression; protein expression; research study; scaffold; side effect; snail protein; success; targeted treatment; therapeutic target; transcription factor; tumor; tumor progression

Project Summary: Despite large improvements in breast cancer therapy, toxic side effects from chemotherapy are a major limitation; thus, it is necessary to develop novel therapeutic strategies that specifically target cancer cells while sparing healthy cells. One hallmark of cancer cells is the “Warburg Effect,” a phenomenon where cancer cells exhibit accelerated glucose metabolism in the presence of oxygen. Hexokinase catalyzes the first committed step in glucose metabolism by phosphorylating glucose to glucose-6-phosphate and thereby trapping glucose in the cell to be used in various downstream pathways. Previous research has demonstrated that while normal mammary gland cells do not express the hexokinase 2 (HK2) isoform, it is highly overexpressed in breast cancer cells, which, in part, is responsible for the accelerated glucose utilization in primary tumors. HK2 deletion inhibits the tumorigenicity of cancer cells in vitro and in vivo. More importantly, systemic deletion of HK2 after tumor onset inhibits tumor development without any adverse physiological consequences in mouse models of cancer. Specifically, HK1 expression levels are sufficient for normal cellular function, but the cancer cells cannot overcome the loss of HK2. As a result, HK2 appears to be a good potential target for therapeutic treatment of primary breast cancer tumors. However, metastasis accounts for the high mortality rate in breast cancer, which makes it more important to elucidate the role HK2 has in breast cancer metastasis. In fact, preliminary results showing that systemic deletion of HK2 after tumor onset in a mouse model of breast cancer metastasis profoundly inhibits metastasis. The proposed research plan will help elucidate the specific mechanism(s) for HK2's role in breast cancer metastasis. The level of HK2 expression dramatically affects to the level of epithelial mesenchymal transition (EMT) protein expression, specifically the important transcription factor SNAIL. In addition, HK2 acts as scaffold to promote the phosphorylation and subsequent inactivation Glycogen Synthase Kinase 3 (GSK3β). SNAIL is phosphorylated by GSK3β, which it turn leads to the degradation of SNAIL. SNAIL is also regulated by O-GlcNAc modification, which helps to stabilize the protein level by suppressing its GSK3β phosphorylation-mediated degradation. Aim 1 will investigate the mechanism for HK2's role in EMT regulation. Furthermore, it is possible that breast cancer cells upregulate HK2 to combat the increased energetic stress that occurs during metastasis. Research has shown that anti-oxidants can enhance the metastatic potential in various cancers. The upregulation of HK2 can increase metabolite flux through the pentose phosphate pathway for NADPH, thereby allowing cells to recycle anti-oxidants, such as gluthathione. Aim 2 will determine HK2's role in intracellular levels of reactive oxygen species in relation to breast cancer metastasis. Overall, this study utilizes a comprehensive approach to elucidate the mechanism(s) for HK2's role in breast cancer metastasis and as a result will provide a new potential therapeutic target.

项目摘要： 尽管乳腺癌疗法有很大改善，但化学疗法的毒性副作用是主要的 局限性;因此，有必要制定新颖的治疗策略，专门针对癌细胞，而 保留健康的细胞。癌细胞的一个标志是“沃伯格效应”，这是一种现象，其中癌细胞 在存在氧气的情况下，暴露的加速葡萄糖代谢。己糖酶催化第一个投入 通过将葡萄糖磷酸化至6-磷酸葡萄糖，从而捕获葡萄糖，从而促进葡萄糖代谢 在细胞中用于各种下游途径。先前的研究表明，虽然正常 乳腺细胞不表达己糖激酶2（HK2），它在乳房中高表达 癌细胞（部分原因）负责原发性肿瘤的加速葡萄糖利用。 HK2 缺失在体外和体内抑制癌细胞的肿瘤性。更重要的是，系统性删除 肿瘤发作后的HK2抑制肿瘤的发育，而没有任何不良生理后果 癌症模型。具体而言，HK1表达水平足以达到正常的细胞功能，但是癌症 细胞无法克服HK2的损失。结果，HK2似乎是治疗的良好潜在目标 治疗原发性乳腺癌肿瘤。但是，转移占乳房的高死亡率 癌症，这使得阐明HK2在乳腺癌转移中的作用变得更加重要。实际上， 初步结果表明，在乳腺癌的小鼠模型中肿瘤发作后的全身缺失 转移深刻抑制转移。拟议的研究计划将有助于阐明特定 HK2在乳腺癌转移中作用的机制。 HK2表达的水平极大地影响 上皮间质转变（EMT）蛋白表达的水平，特别是重要转录 因子蜗牛。另外，HK2充当支架，可促进磷酸化和随后的失活 糖原合酶激酶3（GSK3β）。蜗牛被GSK3β磷酸化，它转向 蜗牛的退化。蜗牛还受O-GLCNAC修饰调节，这有助于稳定蛋白质 通过抑制其GSK3β磷酸化介导的降解水平。 AIM 1将调查机制 对于HK2在EMT调节中的作用。此外，乳腺癌细胞可能会上调HK2以对抗 转移期间发生的能量应力增加。研究表明，抗氧化剂可以 增强各种癌症的转移潜力。 HK2的上调可以增加代谢物通量 通过NADPH的戊糖磷酸途径，从而使细胞能够回收抗氧化剂，例如 谷胱甘肽。 AIM 2将确定HK2在反应性氧中的细胞内水平中的作用 乳腺癌转移。总体而言，这项研究利用一种综合方法来阐明机制 对于HK2在乳腺癌转移中的作用，因此将提供一个新的潜在治疗靶标。