Transcriptional and post-transcriptional mechanisms for lysophosphatidic acid-induced cyclooxygenase-2 expression in ovarian cancer cells.

Emerging evidence suggests that lysophosphatidic acid (LPA) is a physiological regulator of cyclooxygenase-2 (Cox-2) expression. Herein we used ovarian cancer cells as a model to investigate the molecular mechanisms that link the LPA G protein-coupled receptors (GPCRs) to Cox-2 expression. LPA stimulated Cox-2 expression and release of prostaglandins though the LPA(1), LPA(2), and LPA(5) receptors. The effect of LPA involves both transcriptional activation and post-transcriptional enhancement of Cox-2 mRNA stability. The consensus sites for C/EBP in the Cox-2 promoter were essential for transcriptional activation of Cox-2 by LPA. The NF-kappaB and AP-1 transcription factors commonly involved in inducible Cox-2 expression were dispensable. Dominant-negative C/EPBbeta inhibited LPA activation of the Cox-2 promoter and expression. Furthermore, LPA stimulated C/EBPbeta phosphorylation and activity through a novel mechanism integrating GPCR signals and a permissive activity from a receptor tyrosine kinase (RTK). This role of RTK was not consistent with LPA activation of C/EBP through transactivation of RTK, as full activation of RTKs with their own agonists only weakly stimulated C/EBP. In addition to the transcriptional activation, the RNA stabilization protein HuR bound to and protected Cox-2 mRNA in LPA-stimulated cells, indicating an active role for HuR in sustaining Cox-2 induction during physiological responses.