The fuel sensing enzyme AMPK in the pathogenesis of prostate cancer

描述（由申请人提供）：AMPK是一种燃料感应酶，可被激素、细胞因子、运动和减少细胞能量状态（如葡萄糖剥夺）的应激激活。此外，二甲双胍和噻唑烷二酮，用于减少2型糖尿病胰岛素抵抗的药物，已被证明可以激活AMPK。AMPK的激活增加了产生ATP的过程（如脂肪酸氧化），并抑制了其他消耗ATP的过程，如脂肪酸、甘油脂和蛋白质的合成，但不是生存所必需的。相反，当细胞持续过量葡萄糖时，AMPK活性减弱，这些合成过程增强。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来促进其侵袭性生长和存活。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）对前列腺癌细胞的生长有明显的选择性抑制。我们还发现这些作用与脂肪酸合成酶（FAS）、乙酰辅酶a羧化酶（ACC）和mTOR的抑制有关。基于这些发现，我们将验证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目的：(1)证实和扩展我们的初步发现，即AMPK活性在前列腺癌细胞中被抑制，并探索这在多大程度上解释了它们的生长/存活增加和细胞代谢改变；(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/或使其退化；(3)评估前列腺癌细胞中外源性脂肪酸的摄取和氧化是否受到损害，如果是，确定导致这些异常的机制，以及AMPK激活或抑制ACC和是否可以逆转这些异常；(4)探讨雄激素与AMPK反向调控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来源的激素（如脂联素和瘦素）激活，这项努力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。

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.