Induction of urokinase-type plasminogen activator by the anthracycline antibiotic in human RC-K8 lymphoma and H69 lung-carcinoma cells

Current evidence has suggested the possible involvement of ROS as signaling messengers in IL-1 beta- or LPS-induced gene expression. We previously rep orted that both IL-1 beta and LPS induce uPA in RC-K8 human lymphoma cells. Here, we provide evidence that ROS-generating anthracycline antibiotics, i ncluding doxorubicin and aclarubicin, upregulate uPA expression in 2 human malignant cell lines, RC-K8 and H69 small-cell lung-carcinoma cells. Both d oxorubicin and aclarubicin markedly increased uPA accumulation in RC-K8- an d H69-conditioned medium in a dose-dependent manner. In each case, maximal induction was observed at a sublethal concentration, i.e., at a concentrati on where cell growth was slightly inhibited. Both doxorubicin and aclarubic in increased uPA mRNA levels, and induction in each case reached the maxima l level 9 hr after stimulation. Doxorubicin barely changed the half-life of uPA mRNA and activated uPA gene transcription. Antioxidants such as NAC an d PDTC inhibited doxorubicin-induced uPA mRNA accumulation. Microarray anal ysis, using Human Cancer CHIP version 2 (Takara Shuzo, Kyoto, Japan), in wh ich 425 human cancer-related genes were spotted on glass plates, revealed t hat uPA is 1 of 3 genes that were clearly upregulated in H69 cells by doxor ubicin stimulation. These findings suggest that the anthracycline induces u PA in human malignant cells by activating gene transcription in which ROS m ay be involved. Therefore, by upregulating uPA expression, the anthracyclin e may influence many biologic cell functions mediated by the uPA/plasmin sy stem. (C) 2001 Wiley-Liss. Inc.