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。

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.