Regulation of lipogenesis by lysophosphatidic acid in ovarian cancer

溶血磷脂酸对卵巢癌脂肪生成的调节

基本信息

批准号：
8333999
负责人：
XIANJUN FANG
金额：
$ 19.51万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-16 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8333999
关键词：
5&apos -AMP-activated protein kinase Ablation Acetyl Coenzyme A Acetyl-CoA Carboxylase Advanced Malignant Neoplasm Anabolism Anorexia Apoptosis Ascites Attenuated Binding Proteins Biological Biological Process Blood Circulation Body Weight decreased Cancer Patient Cancer cell line Cancerous Catabolism Cell Cycle Arrest Commit Energy Metabolism Enzymes Epithelial Cells Epithelium Exhibits Fatigue Fatty Acids Fatty-acid synthase Growth Growth Factor Human Hyperactive behavior Inflammatory Link Lipids Lysophosphatidic Acid Receptors Lysophospholipids Maintenance Malignant Female Reproductive System Neoplasm Malignant Neoplasms Malignant neoplasm of ovary Malonyl Coenzyme A Mediating Mediator of activation protein Metabolism Molecular Mus Normal tissue morphology Nutritional Ovarian Palmitates Pathway interactions Patient Care Patients Peritoneal Fluid Play Protein Dephosphorylation Proteins Regulation Regulatory Element Role Signal Transduction Staging Sterols Tissues Translating Tumor Tissue Tumorigenicity Up-Regulation Xenograft Model cancer cell chemotherapeutic agent cytotoxic dimer in vivo inhibitor/antagonist innovation killings lipid biosynthesis lysophosphatidic acid malignant phenotype meetings neoplastic cell novel outcome forecast ovarian neoplasm receptor expression tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): One of the most common molecular changes in tumor cells is the heightened rate of endogenous lipid synthesis mediated by increased expression and activity of key lipogenic enzymes, primarily fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC). The lipogenic aberration occurs at early stages of tumorigenesis, becomes more pronounced in advanced cancer, and correlates with poor prognosis of patients. Furthermore, tumor cells depend heavily on or are "addicted" to de novo lipid synthesis, irrespective of the nutritional supplies. Inhibitors of FAS and ACC exhibit anti-tumor effects in culture and in mouse xenograft models. However, one barrier to applying these inhibitors to cancer patient care is their non-selective suppression of lipid synthesis in both normal and cancerous tissues, which could deteriorate weight loss, anorexia, fatigue and other cancer-associated complications. In our preliminary studies, lysophosphatidic acid (LPA), a growth factor-like mediator present in ascites of ovarian cancer patients, stimulated de novo lipid synthesis in ovarian cancer cells through regulation of the sterol regulatory element binding protein (SREBP)-FAS and the AMP-activated kinase (AMPK)-ACC pathways. These effects of LPA on SREBP-FAS and AMPK-ACC were absent from normal or immortalized ovarian epithelial cells. Several LPA receptors are abnormally expressed in ovarian cancer compared to the normal ovarian epithelium. We therefore hypothesize that aberrant LPA signaling activates lipogenic pathways to contribute to the malignant phenotype of ovarian cancer cells. Manipulation of LPA signaling could offer an opportunity to attenuate lipid synthesis in a cancer cell-specific manner. The hypothesis will be examined through completion of the following two specific aims: 1) To elucidate the signal transduction mechanism underlying LPA-driven lipogenesis in ovarian cancer cells; and 2) To determine the biological relevance of LPA-mediated lipogenesis to ovarian cancer. We will first identify the LPA receptor(s) and the intracellular intermediates responsible for LPA activation of the SREBP-FAS and AMPK-ACC cascades. Both molecular and pharmacological approaches will be employed to assess the effects of manipulating LPA receptor expression, sterol availability, and energy metabolism. In Aim 2, we will target the involved LPA receptor(s), LPA catabolism and other signaling players identified in Aim 1 to determine the functional impacts of interference with LPA-induced lipogenesis. The mechanism for the upregulation of lipid synthesis in cancer is poorly defined. This study will answer whether LPA is a pathophysiological determinant of the hyperactive lipogenesis in ovarian cancer. The results could be translated into a novel and innovative approach to targeting tumor-specific lipogenesis.

描述（由申请人提供）：肿瘤细胞中最常见的分子变化之一是由关键脂肪生成酶（主要是脂肪酸合成酶（FAS）和乙酰辅酶A羧化酶（ACC）的表达和活性增加介导的内源性脂质合成速率加快））。脂肪生成异常发生在肿瘤发生的早期阶段，在晚期癌症中变得更加明显，并且与患者的不良预后相关。此外，无论营养供应如何，肿瘤细胞都严重依赖或“沉迷于”脂质从头合成。 FAS 和 ACC 抑制剂在培养物和小鼠异种移植模型中表现出抗肿瘤作用。然而，将这些抑制剂应用于癌症患者护理的一个障碍是它们对正常组织和癌组织中脂质合成的非选择性抑制，这可能会恶化体重减轻、厌食、疲劳和其他癌症相关并发症。在我们的初步研究中，溶血磷脂酸（LPA）是卵巢癌患者腹水中存在的一种生长因子样介质，通过调节甾醇调节元件结合蛋白（SREBP）-FAS和AMP 激活激酶 (AMPK)-ACC 途径。 LPA 对 SREBP-FAS 和 AMPK-ACC 的这些影响在正常或永生化卵巢上皮细胞中不存在。与正常卵巢上皮相比，一些 LPA 受体在卵巢癌中异常表达。因此，我们假设异常的 LPA 信号传导激活脂肪生成途径，从而导致卵巢癌细胞的恶性表型。 LPA 信号传导的操纵可以提供以癌细胞特异性方式减弱脂质合成的机会。该假设将通过完成以下两个具体目标来检验：1）阐明卵巢癌细胞中LPA驱动的脂肪生成的信号转导机制； 2) 确定 LPA 介导的脂肪生成与卵巢癌的生物学相关性。我们将首先确定 LPA 受体和负责 SREBP-FAS 和 AMPK-ACC 级联的 LPA 激活的细胞内中间体。将采用分子和药理学方法来评估操纵 LPA 受体表达、甾醇可用性和能量代谢的影响。在目标 2 中，我们将针对目标 1 中确定的相关 LPA 受体、LPA 分解代谢和其他信号传导因子，以确定干扰 LPA 诱导的脂肪生成的功能影响。癌症中脂质合成上调的机制尚不清楚。这项研究将回答 LPA 是否是卵巢癌脂肪生成过度活跃的病理生理学决定因素。这些结果可以转化为一种针对肿瘤特异性脂肪生成的新颖且创新的方法。