Glucose metabolism and ErbB2-mediated cancer progression

描述（由申请人提供）：癌细胞中糖酵解的增加已被广泛接受为支持恶性表型的重要过程。以往的研究表明，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（HSF 1），一种多功能转录因子，在癌细胞的发展和葡萄糖代谢的调节中起着关键作用。癌基因ErbB 2的过表达增加了乳腺癌的转化和侵袭/转移潜能。然而，直到最近才有数据表明ErbB 2与糖酵解增加直接相关。ErbB 2介导的糖酵解的机制和ErbB 2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）ErbB 2的过表达促进人乳腺癌细胞中的糖酵解，2）ErbB 2的过表达转录激活LDH-A并促进糖酵解，3）ErbB 2的过表达通过转录后控制机制上调HSF 1，4）ErbB 2通过HSF 1上调LDH-A，和5）Herceptin，一种ErbB 2靶向抗体，有效抑制代谢调节PI 3 K/Akt/mTOR信号传导和HSF 1表达。 基于先前的报道和我们的初步研究，我们假设在人乳腺癌细胞中ErbB 2通过HSF 1上调LDH-A。该通路在促进ErbB 2介导的糖酵解和癌症发展中起重要作用。抑制糖酵解将至少部分逆转ErbB 2介导的恶性行为，抑制ErbB 2的赫赛汀与糖酵解抑制剂的组合将更好地抑制ErbB 2过表达的乳腺癌细胞。我们将通过以下具体目标来验证这些假设：目的1：研究HSF 1在ErbB 2增强的糖酵解、细胞转化和侵袭中的作用。目的2：研究ErbB 2上调HSF 1表达的机制。目的3：研究HSF 1上调LDH-A的机制。目标4：确定ErbB 2靶向药物与糖酵解抑制剂联合使用是否会增强对ErbB 2过表达乳腺癌转化和侵袭/转移的抑制。 成功完成拟议的研究将提供一个更好的理解ErbB 2增加糖酵解对乳腺癌的转化和侵袭/转移的影响，并将大大增加我们的知识ErbB 2介导的糖酵解的分子机制。此外，从这些研究中获得的对乳腺癌细胞中独特的ErbB 2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ErbB 2过度表达的癌症。 公共卫生相关性：癌基因ErbB 2可能会增强糖酵解，这是癌细胞的标志，从而促进癌症的发展。该项目的目标是确定ErbB 2过表达对改变癌细胞葡萄糖代谢的影响和机制，并利用癌细胞独特的生物能量学，以开发选择性靶向癌细胞的新策略。这些研究对乳腺癌细胞中ErbB 2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ErbB 2过度表达的癌症。

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. PUBLIC HEALTH RELEVANCE: Oncogene ErbB2 may enhance glycolysis, a hallmark of cancer cells, to promote cancer development. The goal of this project is to determine the impact and mechanism of ErbB2 overexpression on altering the glucose metabolism of cancer cells, and to exploit the unique bioenergetics of cancer cells in order to develop novel strategies for selectively targeting cancer cells. New insights into the 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.