1. ¹Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta, GA, USA
2. ²Department of Medical Microbiology and Immunology, Medical University of Ohio, Toledo, OH, USA
3. ³Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta, GA, USA

Correspondence: Dr S Huang, Department of Biochemistry and Molecular Biology, Medical College of Georgia, 1459 Laney Walker Blvd, Augusta, GA 30912, USA. E-mail: shuang@mcg.edu

Received 1 May 2007; Revised 5 July 2007; Accepted 27 July 2007; Published online 27 August 2007.

Abstract

We reported previously that a signaling pathway consisting of G_i-Ras-NF-B mediates lysophosphatidic acid (LPA)-induced urokinase plasminogen activator (uPA) upregulation in ovarian cancer cells. However, it is not clear what signaling components link Ras to nuclear factor (NF)-B for this LPA-induced event. In the present study, we found that treatment of protein kinase C (PKC) inhibitors including conventional PKC (cPKC) inhibitor Gö6976 abolished LPA-induced uPA upregulation in ovarian cancer cell lines tested, indicating the importance of cPKC activity in this LPA-induced event. Indeed, LPA stimulation led to the activation of PKC and Ras–PKC interaction. Although constitutively active mutants of PKC (a cPKC), PKC (a novel PKC (nPKC)) and PKC (an atypical PKC (aPKC)) were all able to activate NF-B and upregulate uPA expression, only dominant-negative PKC mutant attenuated LPA-induced NF-B activation and uPA upregulation. These results suggest that PKC, rather than PKC isoforms in other PKC classes, participates in LPA-induced NF-B activation and uPA upregulation in ovarian cancer cells. To determine the signaling components downstream of PKC mediating LPA-induced uPA upregulation, we showed that forced expression of dominant-negative CARMA3 or silencing CARMA3, Bcl10 and MALT1 with specific siRNAs diminished these LPA-induced events. Furthermore, we demonstrated that PKC/CARMA3 signaling axis is important in LPA-induced ovarian cancer cell in vitro invasion.