batimastat and Sarcoma--Kaposi

Matrix metalloproteinases (MMPs) play important roles in cancer invasion, angiogenesis, and inflammatory infiltration. Kaposi's sarcoma is a highly disseminated angiogenic tumor of proliferative endothelial cells linked to infection by Kaposi's sarcoma-associated herpesvirus (KSHV). In this study, we showed that KSHV infection increased the invasiveness of primary human umbilical vein endothelial cells (HUVEC) in a Matrigel-based cell invasion assay. KSHV-induced cell invasion was abolished by an inhibitor of MMPs, BB-94, and occurred in both autocrine- and paracrine-dependent fashions. Analysis by zymography and Western blotting showed that KSHV-infected HUVEC cultures had increased secretion of MMP-1, -2, and -9. KSHV increased the secretion of MMP-2 within 1 h following infection without upregulating its mRNA expression level. In contrast, the secretion of MMP-1 and -9 was not increased until 6 h after KSHV infection and was correlated with the upregulation of their mRNA expression levels. Promoter analysis by reporter assays and electrophoretic mobility shift assays identified an AP-1 cis-element as the dominant KSHV-responsive site in the MMP-1 promoter. Together, these results suggest that KSHV infection modulates the production of multiple MMPs to increase cell invasiveness and thus contributes to the pathogenesis of KSHV-induced malignancies.

Topics: Autocrine Communication; Cell Transformation, Viral; Cells, Cultured; Collagenases; Endothelial Cells; Gene Expression Regulation, Enzymologic; Herpesvirus 8, Human; Humans; Neoplasm Invasiveness; Neovascularization, Pathologic; Paracrine Communication; Phenylalanine; Protease Inhibitors; Response Elements; RNA, Messenger; RNA, Neoplasm; Sarcoma, Kaposi; Thiophenes; Transcription Factor AP-1; Umbilical Veins; Up-Regulation