Investigating the role of Phosphoenolpyruvate Carboxykinase in colon cancer

研究磷酸烯醇丙酮酸羧激酶在结肠癌中的作用

• 批准号: 9328524
• 负责人: Emily Dina Montal
• 金额: $ 1.87万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2017-09-13
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9328524
• 关键词: Amino Acids; Anions; Area; Bioenergetics; Cancer Etiology; Carbon; Cell Proliferation; Cells; Cessation of life; Citric Acid Cycle; Colon; Colon Carcinoma; Colorectal Cancer; Complex; Data; Death Rate; Dependence; Development; Diabetes Mellitus; Diabetic mouse; Disease; Distress; Enzymes; FRAP1 gene; Fatty Acids; Gluconeogenesis; Glucose; Glutamine; Goals; Growth; Health; In Vitro; Kidney; Knockout Mice; Knowledge; Lactic acid; Lesion; Link; Liver; Malignant Neoplasms; Mediating; Metabolic; Metabolic Diseases; Metabolism; Nodal; Normal Cell; Nucleic Acids; Nutrient; Obese Mice; Obesity; Pathway interactions; Patients; Phosphoenolpyruvate Carboxylase; Physiological; Play; Prevention; Prevention approach; Prevention strategy; Production; Proliferating; Regulation; Relative Risks; Research; Risk; Rodent; Role; Signal Transduction; Testing; Therapeutic; United States; Warburg Effect; Woman; aerobic glycolysis; amino acid metabolism; blood glucose regulation; cancer cell; cancer prevention; carcinogenesis; cell growth; colon carcinogenesis; diabetic; diabetic patient; flexibility; glucose metabolism; glucose production; in vivo; lipid biosynthesis; lipid metabolism; loss of function; men; mortality; mouse model; novel; patient population; therapeutic target; treatment strategy; tumor; tumor growth; tumor metabolism; tumorigenesis; uptake

Summary: Colorectal cancer is the second leading cause of cancer related deaths among men and women in the United States, even though death rates for colorectal cancer have been declining over the past 20 years, Therefore it is imperative that we determine the underlying mechanisms of the disease in order to increase prevention and treatment strategies. The ability of cancer cells to take up and utilize nutrients is fundamentally different than normal cells. Studies are emerging that highlight an important role for the TCA cycle in regulating cancer cell proliferation. The TCA cycle integrates glucose, amino acid and lipid metabolism depending on cellular needs. In addition, biosynthetic pathways crucial to tumor growth require the TCA cycle for the processing of glucose and glutamine derived carbons. Phosphoenolpyruvate carboxykinase (PEPCK) is well known for its role in gluconeogenesis. Previous studies also show PEPCK is a key regulator of TCA cycle flux. Our lab has demonstrated a role for PEPCK that links metabolic flux and anabolic pathways to cancer cell proliferation. We show that PEPCK promotes cancer cell proliferation in vitro and in vivo and is associated with de novo lipogenesis and nucleic acid synthesis. We also show that the effects of PEPCK on glucose metabolism and cell proliferation are in part mediated via activation of the key growth signaling enzyme, mechanistic target of rapamycin complex 1 (mTORC1). However, it is unclear how PEPCK is mediating this activation. Obesity/diabetes have emerged as a tremendous health concerns in the US and are associated with an increased risk of colon cancer. Studies over the years show that PEPCK expression is elevated in the livers of diabetic patients and rodents. We show in preliminary data that PEPCK is elevated in the colons of obese/diabetic mice. However it is still unknown if PEPCK plays a role mediating the increased colon carcinogenesis associated with obesity. The central hypotheses of this proposal are 1) that PEPCK promotes tumor growth via increasing anabolic metabolism and that 2) PEPCK promotes colon carcinogenesis and is in part responsible for the increased colon cancer associated with obesity/diabetes. These hypotheses will be tested through the following specific aims: 1. Determine whether PEPCK promotes tumor growth via increased anabolic metabolism. 2. Investigate the role of PEPCK in colon carcinogenesis. This research seeks to dissect the mechanism involved in PEPCK induced tumorigenesis, as well as elucidate the role of PEPCK in carcinogenesis under normal physiological conditions as well as metabolic distress to provide new strategies for the prevention and treatment of colorectal cancer.

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