Tyrosine Kinase Signaling in Cancer Cell Metabolism

描述(申请人提供)：Warburg效应描述了一种促肿瘤代谢的转变，即癌细胞比正常组织摄取更多的葡萄糖，但用于氧化磷酸化的葡萄糖更少，即使在有氧的情况下也有利于糖酵解。然而，这对人类癌症的发病机制和疾病进展有多重要仍不清楚。我们通过检查酪氨酸激酶信号--通常在肿瘤中上调--是否调节Warburg效应来促进肿瘤的发生和维持来解决这些问题。这一假说建立在我们的观察基础上，即在表达FGFR1融合酪氨酸激酶的白血病细胞中，糖酵解和氧化磷酸化的一系列关键蛋白质效应因子受酪氨酸磷酸化的调节，这与8p11干细胞骨髓增生性疾病(MPD)有关。这些蛋白因子包括丙酮酸激酶M2(胎儿)亚型(PKM2)、乳酸脱氢酶A(LDH-A)和丙酮酸脱氢酶激酶1(PDHK1)，它们共同作用，严格调控细胞内的代谢途径。因此，我们的总体假设是，致癌的FGFR1通过PKM2、PDHK1和LDH-A的磷酸化以一种急性的方式重新编程癌细胞的代谢，从而促进Warburg效应和肿瘤的发生。在这项提案中，我们将使用表达活性FGFR1融合酪氨酸激酶的癌基因FGFR1相关的8p11MPD和过度表达FGFR1的肺癌作为平台。我们提出了三个具体的目标：(1)阐明FGFR1通过直接磷酸化PKM2、PDHK1和LDH-A来重新编程癌细胞代谢的分子机制；(2)确定FGFR1介导的PKM2、PDHK1和LDH-A的磷酸化是否促进癌细胞从氧化磷酸化向有氧糖酵解的代谢转换；(3)确定FGFR1介导的PKM2、PDHK1和LDH-A的磷酸化是否对肿瘤细胞的增殖和肿瘤的发展提供代谢优势。我们将在小鼠癌症模型中测试上述“挽救”细胞系对糖酵解增殖的依赖性和形成肿瘤的能力。 与公共健康相关：Warburg效应描述了一种促致癌代谢的转变，即癌细胞比正常组织摄取更多的葡萄糖，但用于氧化磷酸化的葡萄糖更少，即使在氧气存在的情况下也有利于糖酵解。然而，这对人类癌症的发病机制和疾病进展有多重要仍不清楚。我们的总体假设是，致癌的FGFR1通过PKM2、PDHK1和LDH-A等代谢酶的酪氨酸磷酸化来规划癌细胞的代谢，以促进Warburg效应和肿瘤生长。

DESCRIPTION (provided by applicant): The Warburg effect describes a pro-oncogenic metabolism switch that cancer cells take up more glucose than normal tissue, yet use less glucose for oxidative phosphorylation and favor glycolysis even in the presence of oxygen. However, how crucial this is for pathogenesis and disease progression in human cancers remains unknown. We approached these questions by examining whether tyrosine kinase signaling - commonly upregulated in tumors - regulates the Warburg effect to contribute to tumorigenesis and maintenance of the tumor. This hypothesis builds on our observation that a spectrum of key protein effectors of glycolysis and oxidative phosphorylation are regulated by tyrosine phosphorylation in leukemia cells expressing FGFR1 fusion tyrosine kinases, which are associated with 8p11 stem cell myeloproliferative disorder (MPD). These protein factors include pyruvate kinase M2 (fetal) isoform (PKM2), lactate dehydrogenase A (LDH-A), and pyruvate dehydrogenase kinase 1 (PDHK1), which work together to tightly regulate the metabolic pathways in cells. Thus, our overall hypothesis is that oncogenic FGFR1 promotes the Warburg effect and tumorigenesis by reprogramming cancer cell metabolism in an acute way via phosphorylation of PKM2, PDHK1 and LDH-A. In this proposal, we will use oncogenic FGFR1-associated 8p11 MPD expressing active FGFR1 fusion tyrosine kinases and lung cancer overexpressing FGFR1 as platforms. Three Specific Aims are proposed: (1) To elucidate the molecular mechanisms by which FGFR1 reprograms cancer cell metabolism through direct phosphorylation of PKM2, PDHK1 and LDH-A; (2) To determine whether FGFR1-mediated phosphorylation of PKM2, PDHK1 and LDH-A promotes the metabolic switch to aerobic glycolysis from oxidative phosphorylation in cancer cells; (3) To determine whether FGFR1-mediated phosphorylation of PKM2, PDHK1 and LDH-A provides a metabolic advantage to tumor cell proliferation and tumor development. We will test the aforementioned "rescue" cell lines for dependence on glycolysis to proliferate and ability to form tumors in murine models of cancer. PUBLIC HEALTH RELEVANCE: The Warburg effect describes a pro-oncogenic metabolism switch that cancer cells take up more glucose than normal tissue, yet use less glucose for oxidative phosphorylation and favor glycolysis even in the presence of oxygen. However, how crucial this is for pathogenesis and disease progression in human cancers remains unknown. Our overall hypothesis is that oncogenic FGFR1 programs cancer cell metabolism through tyrosine phosphorylation of metabolic enzymes including PKM2, PDHK1 and LDH-A to promote the Warburg effect and tumor growth.