EXPRESSION OF UROKINASE-TYPE PLASMINOGEN-ACTIVATOR, ITS RECEPTOR AND TYPE-1 PLASMINOGEN-ACTIVATOR INHIBITOR IS DIFFERENTLY REGULATED BY INHIBITORS OF PROTEIN-SYNTHESIS IN HUMAN CANCER CELL-LINES

Expression of the various components of the plasminogen activation sys tem is under tight regulation by hormones, cytokines, and growth facto rs under physiologic conditions. Like early-response genes, these comp onents are modulated by inhibitors of protein synthesis in some cell l ines. To clarify the specific expression and regulation of mRNAs for u rokinase (uPA), its receptor (uPAR), and type-1 plasminogen activator inhibitor (PAI-1), I analyzed RNA from four human cancer cell lines by RNA blotting after treatment with cycloheximide, anisomycin, emetine or puromycin. These inhibitors, all of which induced translational arr est, induced a very diverse response in the various transcripts, sugge sting that the inhibitors mediate their effects through different mole cular mechanisms, Dose-response analysis showed that, in A549 cells, a nisomycin strongly induced uPAR and PAI-1 mRNA at concentrations that did not cause complete inhibition of protein synthesis, whereas cycloh eximide induced these transcripts in a dose-dependent manner only at c oncentrations sufficient to inhibit total protein synthesis by >90%. P uromycin induced the 3.4-kb transcript of PAI-1 mRNA in A549 and RD ce lls, whereas it decreased the expression of both the 3.4-kb and 2.4-kb PAI-1 transcripts in HT-1080 cells, Different time patterns of induct ion for uPA, uPAR and PAI-1 mRNA suggest that even in the same cell ty pe, inhibitors of protein synthesis mediate their effects on various g enes through different mechanisms. Thus, induction of uPA, uPAR and PA I-1 transcripts by inhibitors of protein synthesis was dependent on th e gene, the cell line, and the type of inhibitor, and inhibition of pr otein synthesis per se was not sufficient for induction of these trans cripts.