Abstract B22: Beta-arrestin2-CARMA3 signaling axis plays critical roles in lysophosphatidic acid-induced ovarian cancer migration and invasion

Abstract

Abstract Ovarian cancer is ranked as the 4th most common type of cancer among women in the United States. Lysophosphatidic acid (LPA) is the diagnostic marker of ovarian cancer. It is significantly elevated in 90% of ovarian cancer patients. Moreover, LPA receptors are aberrantly up-regulated in ovarian cancer patients. LPA is a type of G protein-coupled receptor ligand. In our previous studies, we have demonstrated that a signaling axis consisting of beta-arrestin 2 and CARMA3 (CARD and MAGUK domain-containing protein 3) is required in LPA-induced nuclear factor kappa B (NF-κB) activation in mouse embryonic fibroblast cells. NF-κB is an important transcription factor, which has been proven to mediate LPA-induced ovarian cancer migration and invasion. In this study, we further investigated whether the beta-arrestin2-CARMA3 signaling axis plays a significant role in LPA-induced ovarian cancer cell migration and invasion. Using beta-arrestin 2 and CARMA3 shRNA, we knockdowned their protein expression levels in ovarian cancer cell lines. Consistent with previous reports, we found that down-regulation of beta-arrestin 2 and CARMA3 abolished LPA-induced IKK activity and NF-κB activation in ovarian cancer cells. In addition, in vitro transwell migration and matrigel invasion assays demonstrated that beta-arrestin 2 and CARMA3 shRNA significantly impaired LPA-induced ovarian cancer cell motility and invasiveness. Together, our results provide the evidence that beta-arrestin 2 and CARMA3 serve as critical regulators in LPA-induced, NF-κB-mediated ovarian cancer migration and invasion. Therefore, we speculate that beta-arrestin 2 and CARMA3 may represent attractive therapeutic targets for ovarian cancer and many other types of malignancies. Citation Information: Clin Cancer Res 2010;16(7 Suppl):B22