Fatty Acid Synthase, Caveolin-1 and Membrane Microdomains in Prostate Cancer

前列腺癌中的脂肪酸合酶、Caveolin-1 和膜微结构域

基本信息

批准号：
7664469
负责人：
Dolores Di Vizio
金额：
$ 13.66万
依托单位：
BOSTON CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2010-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7664469
关键词：
1-Phosphatidylinositol 3-Kinase Acylation Androgens Animal Model Apoptotic Behavior Binding Biological Cell Survival Cell membrane Cellular Membrane Characteristics Cholesterol Collaborations Complex Data Disease Progression Endocytosis Environment Enzymes Epidermal Growth Factor Receptor Fatty Acids Fatty-acid synthase Growth Human Link Lipids Liquid substance Location Malignant - descriptor Malignant Neoplasms Malignant neoplasm of prostate Mediating Mediator of activation protein Membrane Membrane Lipids Membrane Microdomains Membrane Proteins Membrane Transport Proteins Metastatic to Modeling Mus Nature Neoplasm Metastasis Oncogenic Pathway interactions Phosphotransferases Play Process Production Prostate Proteins Publishing Reporting Research Personnel Role SRC gene Saturated Fatty Acids Serum Markers Signal Transduction Signaling Molecule Solid Neoplasm System Testing Therapeutic Intervention Time Vesicle cancer cell caveolin 1 in vivo insight lipid transport mutant neoplastic cell non-genomic overexpression palmitoylation prognostic indicator programs research study tumor tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Fatty Acid Synthase (FAS), a major lipogenic enzyme, and Caveolin-1 (Cav-1), a membrane protein that transports cholesterol and regulates signal transduction, are both over-expressed in human and animal models of prostate cancer (PCa). Both proteins exert an oncogenic function in PCa cells. Now, for the first time, we have acquired preliminary results demonstrating that FAS and Cav-1 interact in PCa cells and that FAS, a cytosolic protein, can be induced to associate with cholesterol-rich, lipid raft membranes. Further data show that complex formation between the two proteins is impaired in a Cav-1 mutant deficient in palmitoylation. We also have evidence suggesting that Cav-1 palmitoylation may play a role in signal transduction and that EGFR activation of aggressive PCa cells results in rapid formation of membrane vesicles that contain lipid raft components as well as membrane Cav-1. Because Cav-1 is a circulating marker for aggressive PCa, these secreted vesicles may be linked to metastatic dissemination. Finally, we have acquired evidence indicating that Cav-1 and FAS inhabit similar subcellular locations in human tumors, allowing for cooperation between the two proteins in vivo. In the experiments outlined in this project, we will challenge the following overall hypothesis: Cav-1 and FAS collaborate to alter the lipid raft compartment, contributing to a membrane environment that is richer in cholesterol and saturated fatty acids. These changes in cell membranes may exert important functional consequences on tumor cell survival, growth and other malignant behaviors. Cav-1 and FAS colocalization might also be a useful prognostic indicator. The specific aims of the study are: Aim 1: Determine whether Fatty Acid Synthase and Caveolin-1 collaborate to alter membrane composition and membrane dynamics in PCa cells. We will test the hypotheses that: (i) Activation of c-Src determines FAS localization at the membrane, and FAS and Cav-1 co-localize at the plasma membrane and/or at other cellular membranes, (ii) FAS and Cav-1 alter membrane composition and dynamics, (iii) FAS plays a role in protein palmitoylation. Aim 2: Determine the biological significance of Fatty Acid Synthase and Caveolin-1 colocalization at cell membranes in PCa. We will test the hypotheses that: (i) FAS localization at the membrane is oncogenic. (ii) FAS and Cav-1 co-localization stratifies human tumors with respect to biological behavior, (iii) FAS and Cav-1 collaborate to mediate the secretion of Cav-1-containing vesicles. We believe these experiments will provide new insights into the role of Cav-1 and FAS in PCa and will expand our understanding of the nature, the extent, and the biological significance of membrane lipid changes relevant to oncogenesis in PCa and possibly other malignancies.

描述（由申请人提供）：脂肪酸合酶（FAS）（一种主要的脂肪生成酶）和 Caveolin-1（Cav-1）（一种转运胆固醇和调节信号转导的膜蛋白）在人类和动物模型中均过度表达前列腺癌（PCa）。这两种蛋白在 PCa 细胞中均发挥致癌功能。现在，我们首次获得了初步结果，证明 FAS 和 Cav-1 在 PCa 细胞中相互作用，并且 FAS（一种胞质蛋白）可以被诱导与富含胆固醇的脂筏膜结合。进一步的数据表明，在棕榈酰化缺陷的 Cav-1 突变体中，两种蛋白质之间的复合物形成受到损害。我们还有证据表明，Cav-1 棕榈酰化可能在信号转导中发挥作用，并且侵袭性 PCa 细胞的 EGFR 激活会导致含有脂筏成分和膜 Cav-1 的膜囊泡快速形成。由于 Cav-1 是侵袭性 PCa 的循环标志物，因此这些分泌的囊泡可能与转移性播散有关。最后，我们获得的证据表明 Cav-1 和 FAS 在人类肿瘤中存在相似的亚细胞位置，从而允许两种蛋白质在体内协同作用。在本项目概述的实验中，我们将挑战以下总体假设：Cav-1 和 FAS 协作改变脂筏隔室，从而形成富含胆固醇和饱和脂肪酸的膜环境。细胞膜的这些变化可能对肿瘤细胞的存活、生长和其他恶性行为产生重要的功能影响。 Cav-1 和 FAS 共定位也可能是一个有用的预后指标。该研究的具体目标是：目标 1：确定脂肪酸合酶和 Caveolin-1 是否协同改变 PCa 细胞的膜组成和膜动力学。我们将测试以下假设：（i）c-Src 的激活决定 FAS 在膜上的定位，并且 FAS 和 Cav-1 在质膜和/或其他细胞膜上共定位，（ii）FAS 和 Cav- 1 改变膜组成和动力学，(iii) FAS 在蛋白质棕榈酰化中发挥作用。目标 2：确定 PCa 细胞膜上脂肪酸合酶和 Caveolin-1 共定位的生物学意义。我们将测试以下假设：(i) FAS 定位在膜上具有致癌性。 (ii) FAS 和 Cav-1 共定位根据生物学行为对人类肿瘤进行分层，(iii) FAS 和 Cav-1 协作介导含有 Cav-1 的囊泡的分泌。我们相信这些实验将为 Cav-1 和 FAS 在 PCa 中的作用提供新的见解，并将扩大我们对与 PCa 和可能的其他恶性肿瘤发生相关的膜脂变化的性质、程度和生物学意义的理解。