The fuel sensing enzyme AMPK in the pathogenesis of prostate cancer

前列腺癌发病机制中的燃料感应酶 AMPK

基本信息

批准号：
7997856
负责人：
Zhijun Luo
金额：
$ 1.46万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-27 至 2011-07-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): AMPK is a fuel sensing enzyme that is activated by hormones, cytokines, exercise, and stresses that diminish cellular energy state (e.g., glucose deprivation). In addition, metformin and thiozolidinediones, agents used to diminish insulin resistance in type 2 diabetes, have been shown to activate AMPK. Activation of AMPK increases processes that generate ATP (e.g., fatty-acid oxidation) and restrains others such as fatty acid-, glycerolipid- and protein-synthesis that consume ATP, but not acutely necessary for survival. Conversely, when cells are presented with a sustained excess of glucose, AMPK activity diminishes and these synthetic processes are enhanced. Investigations by others have demonstrated that prostate cancer cells require high rates of fatty acid and protein synthesis for their invasive growth and survival. In preliminary studies, we have observed an apparently selective inhibition of the growth of prostate cancer cells by three distinct AMPK activators, AICAR, rosiglitazone, and metformin. We have also found that these effects are associated with inhibition of fatty acid synthase (FAS), acetyl CoA carboxylase (ACC) and mTOR. Based on these findings, we will test the hypothesis that AMPK activation restricts the growth of prostate cancer cells by altering an array of cellular events. We will carry out studies with the following aims: (1) To confirm and extend our preliminary finding that AMPK activity is suppressed in prostate cancer cells and to explore to what extent this accounts for their increased growth/survival and altered cellular metabolism; (2) To determine whether agents that inhibit prostate cancer cell growth in vitro prevents the growth of prostate cancer xenografts and/or cause their regression; (3) To assess whether the uptake and oxidation of exogeneous fatty acids are imparied in prostate cancer cells, and if so to determine the mechanism(s) responsible for these abnormalities, and whether they are reversed by AMPK activation or inhibition of ACC and; (4) To explore the molecular mechanisms by which androgen and AMPK oppositely regulate the mTOR signaling pathway. Since AMPK can be activated by several anti-diabetic drugs and by certain adipocyte-derived hormones (e.g. adiponectin and leptin), success in this effort would suggest a novel, yet practical approach for treating prostate cancers in humans.

描述（由申请人提供）：AMPK 是一种能量感应酶，可被激素、细胞因子、运动和降低细胞能量状态（例如葡萄糖剥夺）的压力激活。此外，用于减少 2 型糖尿病胰岛素抵抗的药物二甲双胍和噻唑烷二酮类药物已被证明可以激活 AMPK。 AMPK 的激活会增加产生 ATP 的过程（例如脂肪酸氧化），并抑制其他消耗 ATP 的过程，例如脂肪酸、甘油脂和蛋白质的合成，但这些过程对于生存来说并不是急需的。相反，当细胞持续摄入过量的葡萄糖时，AMPK 活性就会减弱，这些合成过程就会增强。其他人的研究表明，前列腺癌细胞需要高速率的脂肪酸和蛋白质合成才能实现侵袭性生长和存活。在初步研究中，我们观察到三种不同的 AMPK 激活剂 AICAR、罗格列酮和二甲双胍明显选择性抑制前列腺癌细胞的生长。我们还发现这些作用与抑制脂肪酸合酶 (FAS)、乙酰辅酶 A 羧化酶 (ACC) 和 mTOR 有关。基于这些发现，我们将检验 AMPK 激活通过改变一系列细胞事件来限制前列腺癌细胞生长的假设。我们将开展以下研究：（1）证实和扩展我们的初步发现，即前列腺癌细胞中AMPK活性受到抑制，并探讨这在多大程度上解释了前列腺癌细胞生长/存活的增加和细胞代谢的改变； (2) 确定体外抑制前列腺癌细胞生长的药物是否能阻止前列腺癌异种移植物的生长和/或导致其消退； (3) 评估前列腺癌细胞中外源脂肪酸的摄取和氧化是否受到损害，如果是，则确定导致这些异常的机制，以及它们是否通过 AMPK 激活或 ACC 抑制而逆转； (4)探讨雄激素与AMPK反向调节mTOR信号通路的分子机制。由于 AMPK 可以被几种抗糖尿病药物和某些脂肪细胞衍生的激素（例如脂联素和瘦素）激活，因此这项工作的成功将为治疗人类前列腺癌提供一种新颖而实用的方法。