
<ArticleTitle>Induction of <prot>urokinase</prot>-type <prot><prot>plasminogen</prot> activator</prot> by the anthracycline antibiotic in human RC-K8 lymphoma and H69 lung-carcinoma cells.</ArticleTitle>
<AbstractText>Current evidence has suggested the possible involvement of ROS as signaling messengers in <prot>IL-1beta</prot>- or LPS-induced gene expression. We previously reported that both <prot>IL-1beta</prot> and LPS induce <prot>uPA</prot> in RC-K8 human lymphoma cells. Here, we provide evidence that ROS-generating anthracycline antibiotics, including doxorubicin and aclarubicin, upregulate <prot>uPA</prot> expression in 2 human malignant cell lines, RC-K8 and H69 small-cell lung-carcinoma cells. Both doxorubicin and aclarubicin markedly increased <prot>uPA</prot> accumulation in RC-K8- and H69-conditioned medium in a dose-dependent manner. In each case, maximal induction was observed at a sublethal concentration, i.e., at a concentration where cell growth was slightly inhibited. Both doxorubicin and aclarubicin increased <prot>uPA</prot> mRNA levels, and induction in each case reached the maximal level 9 hr after stimulation. Doxorubicin barely changed the half-life of <prot>uPA</prot> mRNA and activated <prot>uPA</prot> gene transcription. Antioxidants such as NAC and PDTC inhibited doxorubicin-induced <prot>uPA</prot> mRNA accumulation. Microarray analysis, using Human Cancer CHIP version 2 (Takara Shuzo, Kyoto, Japan), in which 425 human cancer-related genes were spotted on glass plates, revealed that <prot>uPA</prot> is 1 of 3 genes that were clearly upregulated in H69 cells by doxorubicin stimulation. These findings suggest that the anthracycline induces <prot>uPA</prot> in human malignant cells by activating gene transcription in which ROS may be involved. Therefore, by upregulating <prot>uPA</prot> expression, the anthracycline may influence many biologic cell functions mediated by the <prot>uPA</prot>/<prot>plasmin</prot> system.</AbstractText>
