Mouse Models to Evaluate the Role of Pyruvate Kinase Regulation in Cancer Biology

描述（由申请人提供）：即使在有氧条件下，癌细胞也主要利用糖酵解代谢来产生能量。目前尚不清楚这种从氧化代谢到糖酵解代谢的转变是否是细胞生长和/或转化所必需的，或者是肿瘤发生所必需的其他细胞变化的结果。转化细胞的表达谱表明，代谢基因是上调最强烈的基因组之一。在癌细胞中表达增加的糖酵解酶中，有限速糖酵解酶丙酮酸激酶的M2亚型。与大多数表达M1亚型的成人组织相反，迄今为止研究的所有癌细胞都只表达丙酮酸激酶的M2亚型（PK-M2）。PK-M2是建立癌细胞独特代谢所必需的。此外，PK-M2的酶活性受基于酪氨酸激酶的生长信号调节。这项拟议的研究旨在确定PK-M2对体内肿瘤形成和肿瘤维持的重要性。它还将定义基于酪氨酸激酶的信号传导在调节PK-M2活性中的重要性，并确定这种调节如何有助于癌症生物学。这些研究将极大地推进我们对癌症糖酵解调节的理解，并且对于确定如何靶向能量代谢以治疗癌症患者非常重要。 相关性：细胞代谢的差异形成了癌症和正常组织之间的关键区别，尚未用于治疗人类癌症。这项研究将测试改变癌症组织中代谢调节的后果，并将提供一个模型系统来开发靶向代谢途径的药物，这些药物可能会改变患者治疗癌症的方式。

DESCRIPTION (provided by applicant): Even under aerobic conditions, cancer cells utilize primarily glycolytic metabolism to generate energy. It remains unclear if this shift from oxidative to glycolytic metabolism is required for cell growth and/or transformation, or occurs as a consequence of other cellular changes that are necessary for tumorigenesis. Expression profiling of transformed cells demonstrates that metabolic genes are among the most strongly upregulated groups of genes. Among the glycolytic enzymes with increased expression in cancer cells is the M2 isoform of the rate-limiting glycolytic enzyme, pyruvate kinase. In contrast to most adult tissues which express the M1 isoform, all cancer cells studied to date exclusively express the M2 isoform of pyruvate kinase (PK-M2). PK-M2 is necessary for establishing the unique metabolism of cancer cells. In addition, enzymatic activity of PK-M2 is regulated by tyrosine kinase-based growth signals. This proposed research will aim to establish the importance of PK-M2 for tumor formation and tumor maintenance in vivo. It will also define the importance of tyrosine kinase-based signaling in regulating PK-M2 activity, and identify how this regulation contributes to cancer biology. These studies will greatly advance our understanding of glycolytic regulation in cancer and will be important to determine how energy metabolism can be targeted to treat patients with cancer. RELEVANCE: A difference in cellular metabolism forms a key distinction between cancer and normal tissues that has not been exploited to treat human cancer. This study will test the consequences of altering metabolic regulation in cancer tissues, and will provide a model system to develop drugs targeting metabolic pathways that could change the way cancer is treated in patients.