Reactive oxygen species mediate lysophosphatidic acid induced signaling in ovarian cancer cells.

Abstract

Lysophosphatidic acid (LPA) is produced by tumor cells and is present in the ascites fluid of ovarian cancer patients. To determine the role of endogenous LPA in the ovarian cancer cell line SKOV3, we treated cells with the LPA receptor antagonist VPC32183 and found that it inhibited cell growth and induced apoptosis. Exogenous LPA further stimulated ERK and Akt phosphorylation and NF-κB activity. To determine if reactive oxygen species (ROS), which have been implicated as second messengers in cell signaling, were also involved in LPA signaling, we treated cells with the NADPH oxidase inhibitor diphenyleneiodonium (DPI), and antioxidants N-acetyl cysteine, EUK-134 and curcumin, and showed that all blocked LPA-dependent NF-κB activity and cell proliferation. DPI and EUK-134 also inhibited Akt and ERK phosphorylation. LPA was shown to stimulate dichlorofluorescein fluorescence, though not in the presence of DPI, apocynin (an inhibitor of NADPH oxidase), VPC32183, or PEG-catalase. Akt phosphorylation was also inhibited by PEG-catalase and apocynin. These data indicate that NADPH oxidase is a major source of ROS and H(2)O(2) is critical for LPA-mediated signaling. Thus, LPA acts as a growth factor and prevents apoptosis in SKOV3 cells by signaling through redox-dependent activation of ERK, Akt, and NF-κB-dependent signaling pathways.

• Authors: Jerry A Saunders, LeAnn C Rogers, Chananat Klomsiri, Leslie B Poole, Larry W Daniel
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 49 Issue 12 Pg. 2058-67 (Dec 15 2010) ISSN: 1873-4596 [Electronic] United States
• PMID: 20934509 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2010 Elsevier Inc. All rights reserved.

Chemical References

• Antioxidants
• Lysophospholipids
• NF-kappa B
• Onium Compounds
• Organophosphates
• Pyridines
• Reactive Oxygen Species
• Receptors, Lysophosphatidic Acid
• VPC32183
• diphenyleneiodonium
• NADPH Oxidases
• Proto-Oncogene Proteins c-akt
• Extracellular Signal-Regulated MAP Kinases
• lysophosphatidic acid

Topics

• Antioxidants (pharmacology)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• Enzyme Activation (drug effects)
• Epithelial Cells
• Extracellular Signal-Regulated MAP Kinases (metabolism)
• Female
• Genes, Reporter (genetics)
• Humans
• Lysophospholipids (metabolism, pharmacology)
• NADPH Oxidases (antagonists & inhibitors, metabolism)
• NF-kappa B (metabolism)
• Onium Compounds (pharmacology)
• Organophosphates (pharmacology)
• Ovarian Neoplasms (metabolism, pathology)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyridines (pharmacology)
• Reactive Oxygen Species (metabolism)
• Receptors, Lysophosphatidic Acid (antagonists & inhibitors)
• Signal Transduction (drug effects)
• Up-Regulation (drug effects)