Regulation of lipogenesis by lysophosphatidic acid in ovarian cancer

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速率升高，其由关键脂肪生成酶（主要是脂肪酸合酶（FAS）和乙酰辅酶A羧化酶（ACC））的表达和活性增加介导。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，肿瘤细胞严重依赖于或“沉迷于”从头脂质合成，而不管营养供应如何。FAS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。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和癌组织中的脂质合成的非选择性抑制，这可能使体重减轻、厌食、疲劳和其他癌症相关并发症恶化。 在我们的初步研究中，溶血磷脂酸（LPA），生长因子样介质存在于卵巢癌患者的腹水中，刺激从头脂质合成在卵巢癌细胞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。LPA对SREBP-FAS和AMPK-ACC的这些作用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，几种LPA受体在卵巢癌中异常表达。因此，我们假设异常LPA信号激活脂肪生成途径，有助于卵巢癌细胞的恶性表型。LPA信号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;和2）确定LPA介导的脂肪生成与卵巢癌的生物学相关性。 我们将首先鉴定LPA受体和负责LPA激活SREBP-FAS和AMPK-ACC级联的细胞内中间体。将采用分子和药理学方法来评估操纵LPA受体表达、甾醇利用率和能量代谢的影响。在目标2中，我们将靶向目标1中鉴定的相关LPA受体、LPA催化剂和其他信号传导参与者，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。本研究将回答LPA是否是卵巢癌过度脂肪生成的病理生理决定因素。这些结果可以转化为一种新的和创新的方法来靶向肿瘤特异性脂肪生成。 公共卫生相关性：我们最近发现，溶血磷脂酸（LPA），生长因子样介质目前在卵巢癌患者的腹水中的高水平，刺激卵巢癌细胞的从头脂质合成通过激活突出的脂肪生成途径。本申请将确定LPA介导的脂肪生成的机制，并探索其与卵巢肿瘤发生的相关性。拟议研究的完成可能会确定LPA的一种新生物学功能，并提供一种以癌细胞特异性方式颠覆异常脂肪生成的诱人方法。)

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. PUBLIC HEALTH RELEVANCE: We recently found that lysophosphatidic acid (LPA), a growth factor-like mediator present at high levels in ascitic fluids of ovarian cancer patients, stimulates de novo lipid synthesis in ovarian cancer cells via activation of prominent lipogenic pathways. The current application will determine the mechanism for LPA-mediated lipogenesis and explore its relevance to ovarian tumorigenesis. The completion of the proposed studies will likely identify a novel biological function of LPA and offers a tempting approach to subvert the aberrant lipogenesis in a cancer cell-specific manner. )