arachidonyltrifluoromethane and Ovarian-Neoplasms

Defective autophagy and deranged metabolic pathways are common in cancer; pharmacologic targeting of these two pathways could provide a viable therapeutic option. However, how these pathways are regulated by limited availability of growth factors is still unknown. Our study shows that HSulf-1 (endosulfatase), a known tumor suppressor which attenuates heparin sulfate binding growth factor signaling, also regulates interplay between autophagy and lipogenesis. Silencing of HSulf-1 in OV202 and TOV2223 cells (ovarian cancer cell lines) resulted in increased lipid droplets (LDs), reduced autophagic vacuoles (AVs) and less LC3B puncta. In contrast, HSulf-1 proficient cells exhibit more AVs and reduced LDs. Increased LDs in HSulf-1 depleted cells was associated with increased ERK mediated cPLA2

Topics: Animals; Antineoplastic Agents; Arachidonic Acids; Autophagy; Carboplatin; Drug Combinations; Enzyme Inhibitors; Female; Gene Expression Regulation, Neoplastic; Humans; Lipid Droplets; Mice; Ovarian Neoplasms; Phospholipases A2, Cytosolic; RNA, Small Interfering; Signal Transduction; Sulfotransferases; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

In ovarian cancer, the molecular targeted chemotherapeutics could increase the efficiency of low-dose radiotherapy while decreasing injury to adjusted organs. In irradiated A2780 human ovarian carcinoma cells, cytosolic phospholipase A2 (cPLA(2)) inhibitor AACOCF(3) prevented activation of pro-survival Akt signaling and enhanced cell death. The potential molecular mechanisms of this effect could involve signaling through lysophosphatidic acid receptors. In the heterotopic A2780 tumor model using nude mice, cPLA(2) inhibition significantly delayed tumor growth compared to treatment with radiation or vehicle alone. These results identify cPLA(2) as a molecular target to enhance the therapeutic ratio of radiation in ovarian cancer.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Arachidonic Acids; Blotting, Western; Combined Modality Therapy; Cytoplasm; Enzyme Activation; Enzyme Inhibitors; Female; Humans; Mice; Mice, Nude; Ovarian Neoplasms; Phospholipases A2, Cytosolic; Radiation-Sensitizing Agents; Signal Transduction; Xenograft Model Antitumor Assays

Lysophosphatidic acid (LPA) is both a potential marker and a therapeutic target for ovarian cancer. It is critical to identify the sources of elevated LPA levels in ascites and blood of patients with ovarian cancer. We show here that human peritoneal mesothelial cells constitutively produce LPA, which accounts for a significant portion of the chemotactic activity of the conditioned medium from peritoneal mesothelial cells to ovarian cancer cells. Both production of LPA by peritoneal mesothelial cells and the chemotactic activity in the conditioned medium can be blocked by HELSS [an inhibitor of the calcium-independent phospholipase A(2) (iPLA(2))] and AACOCF(3) [an inhibitor of both cytosolic PLA(2) (cPLA(2)) and iPLA(2)]. Moreover, cell-based enzymatic activity assays for PLA(2) indicate that peritoneal mesothelial cells have strong constitutive PLA(2) activity. Receptors for LPA, LPA(2), and LPA(3) are involved in the conditioned medium-induced chemotactic activity. Invasion of ovarian cancer cells into peritoneal mesothelial cells has also been analyzed and shown to require PLA(2), LPA receptors, and the mitogen-activated protein/extracellular signal-regulated kinase kinase/extracellular signal-regulated kinase signaling pathway. Thus, we show here, for the first time, that human peritoneal mesothelial cells constitutively produce bioactive lipid signaling molecules, such as LPA, via iPLA(2) and/or cPLA(2) activities. Conditioned medium from peritoneal mesothelial cells stimulate migration, adhesion, and invasion of ovarian cancer cells, and may play similar roles in vivo.

Topics: Arachidonic Acids; Cell Adhesion; Cell Line, Tumor; Cell Movement; Collagen Type I; Culture Media, Conditioned; Cytosol; Epithelium; Extracellular Signal-Regulated MAP Kinases; Female; Group VI Phospholipases A2; Humans; Isoenzymes; Lysophospholipids; Naphthalenes; Ovarian Neoplasms; Peritoneal Cavity; Peritoneum; Phosphodiesterase Inhibitors; Phospholipases A; Proto-Oncogene Proteins c-akt; Pyrones