Inhibition by galloylglucose (GG6-10) of tumor invasion through extracellular matrix and gelatinase-mediated degradation of type IV collagens by metastatic tumor cells.

Tumor invasion into extracellular matrix (ECM) and basement membrane (BM) is a crucial step in the complex multistage process that leads to metastasis formation. GG6-10 galloylglucose, isolated from Galla Rhois, inhibited the invasion of metastatic HT-1080 cells into a reconstituted BM, such as a Matrigel/fibronectin (FN)-coated filter, in a concentration-dependent fashion. GG6-10 affected neither the tumor cell adhesion and haptotactic migration to ECM components (Matrigel and FN), nor the growth of HT-1080 cells. The gelatin zymography revealed that GG6-10 was able to inhibit not only the degradation of gelatin mediated by matrix metalloproteinases (MMP)-2 and -9 in conditioned medium of HT-1080 tumor cells but also the production of MMP from the tumor cells in a concentration-dependent manner. MMP production is well known to be positively regulated by various cytokines, such as tumor necrosis factor-alpha (TNF-alpha). Thus, we examined the effect of GG6-10 on the TNF-alpha-mediated translation of the MMP-9 gene using HT-1080 cells transfected with the MMP-9 promoter linked to the luciferase gene as a reporter. Similarly to prednisolone, GG6-10 was found to inhibit the TNF-alpha-inducible promoter activity. In keeping with these results, GG6-10 might inhibit tumor cell invasion by inhibiting the gelatinolysis mediated by MMP-2 and -9 and interfering with the production of MMP via inhibiting transcription of the promoter for MMP.