Glucose metabolism and ErbB2-mediated cancer progression

描述(由申请人提供)：癌细胞糖酵解增加已被广泛接受为支持恶性表型的重要过程。以往的报道表明，糖酵解途径中的乳酸脱氢酶A(LDH-A)和多功能转录因子热休克因子1(HSF1)在癌细胞的发育和糖代谢的调节中起着关键作用。癌基因ErbB2的过表达增加了乳腺癌的转化和侵袭/转移潜能。然而，直到最近才出现直接将ErbB2与糖酵解增加联系起来的数据。ErbB2介导的糖酵解的机制以及ErbB2介导的糖酵解在癌症发生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的糖酵解，2)ErbB2的过表达在转录上激活LDH-A并促进糖酵解，3)ErbB2的过表达通过转录后调控机制上调HSF1，4)ErbB2通过HSF1上调LDH-A，5)ErbB2靶向抗体Herceptin有效地抑制代谢调节PI3K/Akt/mTOR信号和HSF1的表达。根据以前的报道和我们的初步研究，我们假设在人类乳腺癌细胞中，ErbB2通过HSF1上调LDH-A。该通路在促进ErbB2介导的糖酵解和肿瘤发生中起着重要作用。抑制糖酵解至少会部分逆转ErbB2介导的恶性行为，而抑制ErbB2的Herceptin与糖酵解抑制剂联合使用将更好地抑制ErbB2过表达的乳腺癌细胞。我们将通过追求以下特定目标来验证这些假设：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：研究ErbB2上调HSF1基因表达的机制。目的：研究HSF1上调LDH-A的作用机制。目的：确定ErbB2靶向药物联合糖酵解抑制剂是否能增强对ErbB2高表达乳腺癌的侵袭和转移的抑制作用。这些研究的成功完成将使我们更好地了解ErbB2糖酵解在乳腺癌转化和侵袭/转移中的作用，并将极大地增强我们对ErbB2介导糖酵解的分子机制的了解。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导致更有效的靶向癌症治疗，以治疗ErbB2过表达的癌症。 公共卫生相关性：癌基因ErbB2可能会促进糖酵解，这是癌细胞的一个标志，以促进癌症的发展。本项目的目标是确定ErbB2过表达对改变癌细胞葡萄糖代谢的影响和机制，并开发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ErbB2介导的乳腺癌细胞代谢的新见解可能会导致一种更有效的靶向癌症治疗方法来治疗ErbB2过表达的癌症。

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.