Lysophosphatidic acid activates lipogenic pathways and de novo lipid synthesis in ovarian cancer cells.
One of the most common molecular changes in cancer is the increased endogenous lipid synthesis, mediated primarily by overexpression and/or hyperactivity of fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC). The changes in these key lipogenic enzymes are critical for the development and maintenance of the malignant phenotype. Previous efforts to control oncogenic lipogenesis have been focused on pharmacological inhibitors of FAS and ACC. Although they show anti-tumor effects in culture and in mouse models, these inhibitors are nonselective blockers of lipid synthesis in both normal and cancer cells. To target lipid anabolism in tumor cells specifically, it is important to identify the mechanism governing hyperactive lipogenesis in malignant cells. In this study, we demonstrate that lysophosphatidic acid (LPA), a growth factor-like mediator present at high levels in ascites of ovarian cancer patients, regulates the sterol regulatory element binding protein-FAS and AMP-activated protein kinase-ACC pathways in ovarian cancer cells but not in normal or immortalized ovarian epithelial cells. Activation of these lipogenic pathways is linked to increased de novo lipid synthesis. The pro-lipogenic action of LPA is mediated through LPA(2), an LPA receptor subtype overexpressed in ovarian cancer and other malignancies. Downstream of LPA(2), the G(12/13) and G(q) signaling cascades mediate LPA-dependent sterol regulatory element-binding protein activation and AMP-activated protein kinase inhibition, respectively. Moreover, inhibition of de novo lipid synthesis dramatically attenuated LPA-induced cell proliferation. These results demonstrate that LPA signaling is causally linked to the hyperactive lipogenesis in ovarian cancer cells, which can be exploited for development of new anti-cancer therapies.
Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, School of Medicine, Richmond, Virginia 23298, USA.
Abir
A
Mukherjee
Jinhua
J
Wu
Suzanne
S
Barbour
Xianjun
X
Fang
D000818:Animals; D045744:Cell Line, Tumor; D064429:Fatty Acid Synthases / Q000096:biosynthesis; D005260:Female; D044365:GTP-Binding Protein alpha Subunits, G12-G13 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D050155:Lipogenesis / Q000187:drug effects*; D008246:Lysophospholipids / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D049368:Receptors, Lysophosphatidic Acid / Q000096:biosynthesis; D050436:Regulatory Elements, Transcriptional; D015398:Signal Transduction / Q000187:drug effects*
D008246:Lysophospholipids; D009363:Neoplasm Proteins; D049368:Receptors, Lysophosphatidic Acid; D064429:Fatty Acid Synthases; D044365:GTP-Binding Protein alpha Subunits, G12-G13; C032881:lysophosphatidic acid