Regulation of lipogenesis by lysophosphatidic acid in ovarian cancer

描述(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肪合成速度加快，这是由关键的脂肪生成酶，主要是脂肪酸合成酶(Fas)和乙酰辅酶A羧基酶(ACC)的表达和活性增加所介导的。成脂异常发生在肿瘤发生的早期阶段，在晚期癌症中更为明显，并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”从头合成脂肪。Fas和ACC的抑制剂在培养和小鼠异种移植模型中显示出抗肿瘤的作用。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症组织中的脂肪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，溶血磷脂酸(LPA)，一种存在于卵巢癌患者腹水中的生长因子样介质，通过调节固醇调节元件结合蛋白(SREBP)-Fas和AMP-激活激酶(AMPK)-ACC途径刺激卵巢癌细胞从头合成脂质。LPA对SREBP-Fas和AMPK-ACC的影响在正常或永生化的卵巢上皮细胞中不存在。与正常卵巢上皮相比，几种LPA受体在卵巢癌中异常表达。因此，我们假设异常的LPA信号激活了造脂途径，从而促进了卵巢癌细胞的恶性表型。操纵LPA信号可以提供一个机会，以一种癌细胞特异性的方式减弱脂质的合成。这一假说将通过完成以下两个特定目标来检验：1)阐明LPA驱动卵巢癌细胞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(S)和负责激活SREBP-Fas和AMPK-ACC级联的LPA的细胞内中间体。分子和药理学方法将被用来评估操纵LPA受体表达、甾醇可利用性和能量代谢的效果。在目标2中，我们将针对目标1中发现的相关LPA受体(S)、LPA分解代谢和其他信号分子，以确定干扰对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是否是卵巢癌过度活跃脂肪生成的病理生理决定因素。这一结果可以转化为针对肿瘤特异性脂肪生成的一种新颖和创新的方法。

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.