Regulation of lipogenesis by lysophosphatidic acid in ovarian cancer

点击翻译按钮获取中文摘要

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. 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. )