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.

项目总结： 尽管乳腺癌的治疗有了很大的改进，但化疗的毒副作用仍是一个主要问题。 因此，有必要开发专门针对癌细胞的新的治疗策略，同时 节省健康的细胞。癌细胞的一个特征是“沃堡效应”，这是一种癌细胞 在氧气存在的情况下表现出葡萄糖代谢加速。己糖激酶催化第一个承诺的 通过将葡萄糖磷酸化为葡萄糖-6-磷酸从而捕获葡萄糖而进入葡萄糖代谢的一步 在用于各种下游通路的细胞中。先前的研究已经证明，虽然正常 乳腺细胞不表达己糖激酶2(HK2)亚型，它在乳腺中高表达 癌细胞，这在一定程度上是加速原发肿瘤中葡萄糖利用的原因。香港2 缺失在体外和体内都能抑制癌细胞的致瘤性。更重要的是，系统性地删除 HK2抑制小鼠肿瘤生长且无任何不良生理后果 癌症的模型。具体地说，HK1的表达水平足以维持正常的细胞功能，但癌症 细胞无法克服HK2的缺失。因此，HK2似乎是一个很好的潜在治疗靶点。 原发乳腺癌肿瘤的治疗。然而，转移是乳房高死亡率的原因。 癌症，这使得阐明HK2在乳腺癌转移中的作用变得更加重要。事实上, 初步结果显示，在乳腺癌小鼠模型中，肿瘤发生后HK2的系统性缺失 转移深刻地抑制了转移。拟议的研究计划将有助于阐明具体的 HK2‘S参与乳腺癌转移的机制(S)HK2的表达水平显著影响TO 上皮间充质转化(EMT)蛋白的表达水平，特别是重要转录 蜗牛的因素。此外，HK2还作为支架促进了磷酸化和随后的失活 糖原合成酶3(GSK3)β。蜗牛被Gsk3β磷酸化，进而导致 蜗牛的退化。Snail也受到O-GlcNAc修饰的调节，这有助于稳定蛋白质 通过抑制其GSK3β磷酸化介导的降解而达到水平。目标1将研究这一机制 为香港2‘S在机电工程监管中所扮演的角色。此外，乳腺癌细胞可能上调HK2以对抗 转移过程中增加的能量压力。研究表明，抗氧化剂可以 增强各种癌症的转移潜能。HK2表达上调可增加代谢产物通量 通过磷酸戊糖途径进行NADPH，从而允许细胞循环使用抗氧化剂，如 谷胱甘肽。目标2将确定HK2‘S在细胞内活性氧水平中的作用与 乳腺癌转移。总体而言，本研究采用了综合的方法来阐明这一机制(S) 对于HK2‘S在乳腺癌转移中的作用，从而将提供一个新的潜在的治疗靶点。