Investigating the role of Phosphoenolpyruvate Carboxykinase in colon cancer

摘要： 在美国，结直肠癌是导致男性和女性癌症相关死亡的第二大原因 在美国，尽管结直肠癌的死亡率在过去20年里一直在下降， 因此，我们必须确定这种疾病的潜在机制，以便增加 预防和治疗策略。癌细胞吸收和利用营养物质的能力从根本上说是 与正常细胞不同。正在涌现的研究强调了三氯乙酸循环在调节 癌细胞增殖。TCA循环整合了葡萄糖、氨基酸和脂肪代谢，这取决于 手机的需求。此外，对肿瘤生长至关重要的生物合成途径需要TCA循环 葡萄糖和谷氨酰胺衍生碳的加工。磷酸烯醇式丙酮酸羧激酶(PEPCK) 以其在糖异生中的作用而闻名。以往的研究还表明，PEPCK是TCA循环通量的关键调节因子。 我们的实验室已经证明了PEPCK的作用，它将代谢流和合成代谢途径与癌细胞联系起来 扩散。我们发现PEPCK在体外和体内都能促进癌细胞的增殖，并与 从头开始脂肪生成和核酸合成。我们还表明，PEPCK对血糖的影响 新陈代谢和细胞增殖在一定程度上是通过激活关键的生长信号酶来调节的， 雷帕霉素复合体1的作用靶点(MTORC1)。然而，尚不清楚PEPCK是如何调解这一问题的 激活。肥胖/糖尿病在美国已经成为一个巨大的健康问题，并与 会增加患结肠癌的风险。多年来的研究表明，PEPCK的表达在 糖尿病患者和啮齿动物的肝脏。我们在初步数据中显示，PEPCK在结肠癌中升高 肥胖/糖尿病小鼠。然而，PEPCK是否起到调节结肠增加的作用仍不清楚 与肥胖有关的致癌因素。这项提议的中心假设是1)PEPCK推动 肿瘤生长通过增加合成代谢和2)PEPCK促进结肠癌的发生和 部分原因是与肥胖/糖尿病相关的结肠癌增加。这些假设将是 通过以下具体目标进行测试：1.确定PEPCK是否通过以下途径促进肿瘤生长 增加合成代谢。2.探讨PEPCK在结肠癌发生中的作用。这项研究 旨在剖析PEPCK诱导肿瘤发生的机制，以及阐明PEPCK的作用 PEPCK在正常生理条件下的致癌以及代谢障碍提供新的 预防和治疗结直肠癌的策略。

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.