SYNERGISTIC INDUCTION OF TISSUE-TYPE PLASMINOGEN-ACTIVATOR EXPRESSIONBY RETINOIDS AND CYCLIC-NUCLEOTIDES IN RAT C6 GLIOMA-CELLS

Background: We have recently shown that 13 cis-retinoic acid (cRA) ind uces tissue-type plasminogen activator (t-PA) production by rat C6 gli oma cells, which are a typical model of human glioma. The production o f t-PA was considered an adverse effect of cRA since it was responsibl e for a fibrinolytic activity-induced intra-glioma haemorrhage. Object ive: This study investigated the mechanism of the t-PA induction by cR A and focused on the interaction between cRA- and (cAMP)-dependent sig nalling pathways. Methods: t-PA antigen level was assayed by an enzyme -linked immuno-absorbant assay (ELISA) method. Northern blots were per formed using 5'-DIG oligonucleotide probes. The synergistic effect was studied using the isobole method of Berenbaum.(1) Results: Retinoic a cid (RA) induced the production of t-PA related to increased levels of t-PA messenger ribonucleic acid (mRNA), The t-PA gene expression invo lved protein synthesis, more particularly the induction of retinoic ac id receptor (RAR beta) which appears to mediate the t-PA induction by cRA in C6 glioma cells. The cAMP-dependent signalling pathway acted sy nergistically to induce t-PA synthesis. The action of cRA must precede the one of cAMP, and cAMP-dependent protein kinase activity is requir ed for the optimal induction of t-PA production by cRA. Conclusion: Kn owledge of the mechanism of cRA-induced t-PA production, mainly the cr oss-talk with the cAMP-dependent signalling pathway, will help in the understanding of the effects of cRA.