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

• 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
• 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' -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

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内源性脂质合成的速率提高，这是由关键脂肪酶的表达和活性增加，主要是脂肪酸合酶（FAS）和乙酰-COA羧化酶（ACC）。脂像差发生在肿瘤发生的早期阶段，在晚期癌症中变得更加明显，并且与患者预后不良有关。此外，无论营养供应如何，肿瘤细胞在很大程度上取决于或对从头脂质的合成而“上瘾”。 FA和ACC的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。但是，将这些抑制剂应用于癌症患者护理中的一个障碍是它们在正常组织和癌组织中对脂质合成的非选择性抑制，这可能会恶化体重减轻，厌食，疲劳和其他与癌症相关的并发症。 在我们的初步研究中，存在于卵巢癌患者腹水中的一种类似生长因子的介体（LPA），通过调节固醇调节元件调节元件结合蛋白（SREBP）-FAS和AMP活化的Kinase（AMPK）-ACCCC-acc tathrowe-acccc-acc pathorey。 LPA对SREBP-FAS和AMPK-ACC的这些影响不存在正常或永生化的卵巢上皮细胞。与正常的卵巢上皮相比，在卵巢癌中，几种LPA受体异常表达。因此，我们假设异常LPA信号传导激活脂肪生成途径，从而有助于卵巢癌细胞的恶性表型。 LPA信号传导的操作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的来检查：1）阐明卵巢癌细胞中LPA驱动的脂肪形成的信号转导机制； 2）确定LPA介导的脂肪形成与卵巢癌的生物学相关性。 我们将首先识别LPA受体以及负责SREBP-FAS和AMPK-ACC级联反应LPA激活的细胞内中间体。将采用分子和药理方法来评估操纵LPA受体表达，固醇可用性和能量代谢的影响。在AIM 2中，我们将针对AIM 1中鉴定的相关LPA受体，LPA分解代谢和其他信号播放器，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的定义很差。这项研究将回答LPA是否是卵巢癌多动脂肪形成的病理生理决定因素。结果可以转化为一种新颖而创新的方法来靶向肿瘤特异性脂肪形成。