Glucose metabolism and ErbB2-mediated cancer progression

葡萄糖代谢和 ErbB2 介导的癌症进展

• 批准号: 8616726
• 负责人: Ming Tan
• 金额: $ 26.9万
• 依托单位: UNIVERSITY OF SOUTH ALABAMA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2016-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8616726
• 关键词: Address; Animal Model; Antibodies; Behavior; Bioenergetics; Breast Cancer Cell; Cancer Patient; Cells; Cycloheximide; Data; Dependency; Development; Enzymes; Glycolysis; Glycolysis Inhibition; Goals; Human; In Vitro; Knowledge; Lead; Link; Malignant - descriptor; Malignant Neoplasms; Mediating; Metabolism; Modeling; Molecular; Neoplasm Metastasis; Normal Cell; Oncogene ErbB2; Oxygen; Pathway interactions; Phosphotransferases; Play; Polyribosomes; Post-Transcriptional Regulation; Process; Protein Biosynthesis; Proteins; Publishing; Regulation; Reporting; Resistance; Roche brand of trastuzumab; Role; Sampling; Signal Pathway; Signal Transduction; Signaling Molecule; Testing; Transcriptional Activation; Translations; Up-Regulation; Work; base; cancer cell; cancer therapy; cell transformation; glucose metabolism; heat-shock factor 1; human FRAP1 protein; inhibitor/antagonist; insight; lactate dehydrogenase A; mTOR Signaling Pathway; malignant breast neoplasm; malignant phenotype; novel strategies; overexpression; public health relevance; transcription factor; tumor progression

DESCRIPTION (provided by applicant): The increased glycolysis in cancer cells has been well accepted to be an important process to support malignant phenotypes. Previous reports have shown that lactate dehydrogenase A (LDH-A), an enzyme in the glycolytic pathway, and heat shock factor 1 (HSF1), a multifunctional transcription factor, play critical roles in cancer cell development and regulation of glucose metabolism. Overexpression of the oncogene ErbB2 increases the transformation and invasion/metastatic potentials of breast cancers. However, only recently has data emerged that directly links ErbB2 to increased glycolysis. The mechanism underling ErbB2-mediated glycolysis and the role of ErbB2-mediated glycolysis in cancer development remains poorly understood. Our preliminary data have demonstrated that: 1) overexpression of ErbB2 promotes glycolysis in human breast cancer cells, 2) overexpression of ErbB2 transcriptionally activates LDH-A and promotes glycolysis, 3) overexpression of ErbB2 upregulates HSF1 through a post-transcriptional control mechanism, 4) ErbB2 upregulates LDH-A through HSF1, and 5) Herceptin, an ErbB2-targeting antibody, effectively inhibits metabolism-regulating PI3K/Akt/mTOR signaling and HSF1 expression. Based on previous reports and our preliminary studies, we hypothesize that in human breast cancer cells ErbB2 upregulates LDH-A through HSF1. This pathway plays an important role in promoting ErbB2-mediated glycolysis and cancer development. Inhibition of glycolysis will at least partially reverse ErbB2-mediated malignant behavior, and the combination of Herceptin, which inhibits ErbB2, with a glycolysis inhibitor will better inhibit ErbB2-overexpressing breast cancer cells. We will test these hypotheses through the pursuit of the following specific aims: Aim 1: To study the role of HSF1 in ErbB2-enhanced glycolysis, cell transformation, and invasion. Aim 2: To study the mechanism of upregulation of HSF1 by ErbB2. Aim 3: To study the mechanism of upregulation of LDH-A by HSF1. Aim 4: To determine whether the combination of an ErbB2- targeting agent with glycolysis inhibitors will enhance inhibition of transformation and invasion/metastasis of ErbB2-overexpressing breast cancers. Successful completion of the proposed studies will provide a better understanding of the impact of ErbB2-increased glycolysis on breast cancer transformation and invasion/metastasis and will substantially augment our knowledge of the molecular mechanisms underlying ErbB2-mediated glycolysis. Furthermore, new insights into the unique ErbB2-mediated metabolism in breast cancer cells that result from these studies may lead to a more effective targeted cancer therapy for treating ErbB2-overexpressing cancers.

描述（由申请人提供）：癌细胞中糖酵解的增加已被广泛认为是支持恶性表型的重要过程。先前的报告表明，乳酸脱氢酶 A (LDH-A)（一种糖酵解途径中的酶）和热休克因子 1 (HSF1)（一种多功能转录因子）在癌细胞发育和葡萄糖代谢调节中发挥着关键作用。癌基因 ErbB2 的过度表达会增加乳腺癌的转化和侵袭/转移潜力。然而，直到最近才出现数据表明 ErbB2 与糖酵解增加直接相关。 ErbB2 介导的糖酵解的机制以及 ErbB2 介导的糖酵解在癌症发展中的作用仍然知之甚少。我们的初步数据表明：1) ErbB2 的过表达促进人乳腺癌细胞中的糖酵解，2) ErbB2 的过表达转录激活 LDH-A 并促进糖酵解，3) ErbB2 的过表达通过转录后控制机制上调 HSF1，4) ErbB2 通过 HSF1 上调 LDH-A，5) Herceptin 是一种 ErbB2 靶向抗体，可有效抑制代谢调节 PI3K/Akt/mTOR 信号传导和 HSF1 表达。 根据之前的报告和我们的初步研究，我们假设在人类乳腺癌细胞中 ErbB2 通过 HSF1 上调 LDH-A。该途径在促进 ErbB2 介导的糖酵解和癌症发展中发挥重要作用。糖酵解的抑制将至少部分逆转 ErbB2 介导的恶性行为，抑制 ErbB2 的赫赛汀与糖酵解抑制剂的组合将更好地抑制 ErbB2 过度表达的乳腺癌细胞。我们将通过追求以下具体目标来检验这些假设： 目标 1：研究 HSF1 在 ErbB2 增强的糖酵解、细胞转化和侵袭中的作用。目的2：研究ErbB2上调HSF1的机制。目的3：研究HSF1上调LDH-A的机制。目标 4：确定 ErbB2 靶向剂与糖酵解抑制剂的组合是否会增强对 ErbB2 过表达乳腺癌的转化和侵袭/转移的抑制。 成功完成拟议的研究将有助于更好地了解 ErbB2 增加的糖酵解对乳腺癌转化和侵袭/转移的影响，并将大大增强我们对 ErbB2 介导的糖酵解分子机制的了解。此外，这些研究对乳腺癌细胞中独特的 ErbB2 介导的代谢的新见解可能会带来更有效的靶向癌症疗法，用于治疗 ErbB2 过度表达的癌症。