Tyrosine Kinase Signaling in Cancer Cell Metabolism

描述（由申请人提供）：瓦尔堡效应描述了一种原癌代谢开关，即癌细胞比正常组织吸收更多的葡萄糖，但使用较少的葡萄糖进行氧化磷酸化，即使在氧气存在下也有利于糖酵解。然而，这对人类癌症的发病机制和疾病进展有多重要仍然未知。我们通过检测酪氨酸激酶信号传导--通常在肿瘤中上调--是否调节瓦尔堡效应以促进肿瘤发生和肿瘤维持来解决这些问题。这一假设建立在我们的观察基础上，即糖酵解和氧化磷酸化的关键蛋白效应物的光谱由表达FGFR 1融合酪氨酸激酶的白血病细胞中的酪氨酸磷酸化调节，所述FGFR 1融合酪氨酸激酶与8 p11干细胞骨髓增生性疾病（MPD）相关。这些蛋白质因子包括丙酮酸激酶M2（胎儿）亚型（PKM 2）、乳酸脱氢酶A（LDH-A）和丙酮酸脱氢酶激酶1（PDHK 1），它们共同作用以紧密调节细胞中的代谢途径。因此，我们的总体假设是致癌FGFR 1通过PKM 2、PDHK 1和LDH-A的磷酸化以急性方式重编程癌细胞代谢来促进瓦尔堡效应和肿瘤发生。在这个提议中，我们将使用致癌的FGFR 1相关的8 p11 MPD表达活性FGFR 1融合酪氨酸激酶和肺癌过表达FGFR 1作为平台。本研究的目的有三个：（1）阐明FGFR 1通过直接磷酸化PKM 2、PDHK 1和LDH-A重编程癌细胞代谢的分子机制;（2）确定FGFR 1介导的PKM 2、PDHK 1和LDH-A的磷酸化是否促进癌细胞代谢从氧化磷酸化转变为有氧糖酵解;（3）确定FGFR 1介导的PKM 2、PDHK 1和LDH-A的磷酸化是否为肿瘤细胞增殖和肿瘤发展提供代谢优势。我们将测试上述“拯救”细胞系对糖酵解的依赖性以在癌症的鼠模型中增殖和形成肿瘤的能力。 公共卫生相关性：瓦尔堡效应描述了一种促癌代谢开关，即癌细胞比正常组织吸收更多的葡萄糖，但使用更少的葡萄糖进行氧化磷酸化，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然未知。我们的总体假设是致癌FGFR 1通过代谢酶包括PKM 2、PDHK 1和LDH-A的酪氨酸磷酸化来编程癌细胞代谢，以促进瓦尔堡效应和肿瘤生长。

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.