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。

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.