Glucose metabolism and ErbB2-mediated cancer progression

葡萄糖代谢和 ErbB2 介导的癌症进展

基本信息

批准号：
9059029
负责人：
Ming Tan
金额：
$ 27.73万
依托单位：
UNIVERSITY OF SOUTH ALABAMA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9059029
关键词：
Address Animal Model Antibodies Behavior Bioenergetics Breast Cancer Cell Breast Cancer Patient Breast cancer metastasis Cells Cycloheximide Data Dependency Development ERBB2 gene Enzymes FRAP1 gene Glycolysis Glycolysis Inhibition Goals Health Human In Vitro Knowledge Lead Link Malignant - descriptor Malignant Neoplasms Mediating Metabolism Modeling Molecular Neoplasm Metastasis Normal Cell Oxygen Pathway interactions Phosphotransferases Play Polyribosomes Post-Transcriptional Regulation Process Protein Biosynthesis Proteins Publishing Regulation Reporting Resistance Role Sampling Signal Pathway Signal Transduction Signaling Molecule Testing Transcriptional Activation Translations Trastuzumab Up-Regulation Work base cancer cell cell transformation glucose metabolism heat-shock factor 1 hypoxia inducible factor 1 inhibitor/antagonist insight knock-down lactate dehydrogenase A mTOR Signaling Pathway malignant breast neoplasm malignant phenotype novel strategies overexpression targeted agent targeted cancer therapy transcription factor tumor progression

项目摘要

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接受，是支持恶性表型的重要过程。先前的报道表明，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的调节中起关键作用。癌基因ERBB2的过表达增加了乳腺癌的转化和侵袭/转移潜力。但是，直到最近才出现了直接将ERBB2与增加糖酵解的数据。 ERBB2介导的糖酵解和ERBB2介导的糖酵解在癌症发育中的作用的机制仍然很少了解。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ERBB2的过表达通过HSF1上调HSF1通过HSF1通过HSF1通过HSF1进行了hsf1，并通过3）和4）erb2-4）和4）luds luds luds luds luds luds luds luds luds lud lud lud lud lud lud luds Herceptin是一种靶向ERBB2的抗体，有效地抑制了代谢调节PI3K/AKT/MTOR信号传导和HSF1表达。根据先前的报告和初步研究，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方面起着重要作用。糖酵解的抑制作用至少将部分反向ERBB2介导的恶性行为，并且抑制ERBB2的赫赛汀与糖酵解抑制剂的组合将更好地抑制对ERBB2过表达的乳腺癌细胞。我们将通过追求以下特定目的来检验这些假设：目标1：研究HSF1在ERBB2增强糖酵解，细胞转化和侵袭中的作用。目标2：研究ERBB2对HSF1上调的机理。目标3：研究HSF1对LDH-A上调的机制。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过表达的乳腺癌的转化和侵袭/转移的抑制作用。成功完成拟议的研究将更好地理解ERBB2增强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介导的糖酵解的分子机制的了解。此外，这些研究引起的乳腺癌细胞中独特的ERBB2介导的代谢的新见解可能会导致更有效的靶向癌症治疗，用于治疗ERBB2过表达的癌症。

项目成果

期刊论文数量（13）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Overcoming trastuzumab resistance in breast cancer by targeting dysregulated glucose metabolism.

DOI：
10.1158/0008-5472.can-11-0127
发表时间：
2011-07-01
期刊：
Cancer research
影响因子：
11.2
作者：
Zhao Y;Liu H;Liu Z;Ding Y;Ledoux SP;Wilson GL;Voellmy R;Lin Y;Lin W;Nahta R;Liu B;Fodstad O;Chen J;Wu Y;Price JE;Tan M
通讯作者：
Tan M

ErbB2-intronic microRNA-4728: a novel tumor suppressor and antagonist of oncogenic MAPK signaling.

DOI：
10.1038/cddis.2015.116
发表时间：
2015-05-07
期刊：
Cell death & disease
影响因子：
9
作者：
Schmitt DC;Madeira da Silva L;Zhang W;Liu Z;Arora R;Lim S;Schuler AM;McClellan S;Andrews JF;Kahn AG;Zhou M;Ahn EY;Tan M
通讯作者：
Tan M

B7-H3 silencing increases paclitaxel sensitivity by abrogating Jak2/Stat3 phosphorylation.

DOI：
10.1158/1535-7163.mct-11-0072
发表时间：
2011-06
期刊：
Molecular cancer therapeutics
影响因子：
5.7
作者：
Liu H;Tekle C;Chen YW;Kristian A;Zhao Y;Zhou M;Liu Z;Ding Y;Wang B;Mælandsmo GM;Nesland JM;Fodstad O;Tan M
通讯作者：
Tan M

Stalling the engine of resistance: targeting cancer metabolism to overcome therapeutic resistance.