HUMAN HEPATOMA-CELLS RICH IN P-GLYCOPROTEIN DISPLAY ENHANCED IN-VITROINVASIVE PROPERTIES COMPARED TO P-GLYCOPROTEIN-POOR HEPATOMA-CELLS

Whether the phenotypes of drug resistance and metastatic activity in c ancer are dependent on each other or not is controversial. We compared in vitro invasive properties of human hepatoma cells resistant to epi rubicin and rich in P-glycoprotein. (Pgp) (HB8065/R) with the parental epirubicin-sensitive, Pgp-poor cells (HB8065/S). The HB8065/R cells d isplayed elevated capacity to migrate in a transwell chamber assay (th ree- to fourfold compared to the HB8065/S cells), both in the absence and presence of a reconstituted basement membrane extract (Matrigel). In the presence of the P-gp inhibitor PSC 833 (1.5 mu g/ml) the capaci ty of the HB8065/R cells to cross Matrigel-coated filters was attenuat ed by similar to 25%. Compared to the HB8065/S cells, the resistant ce ll line expressed higher level of plasminogen activator inhibitor (PAI )-1 mRNA (similar to threefold), which was reflected by a similar to f ivefold increase in secreted PAI-1 immunoactivity (similar to 50 ng/10 (6) HB8065/R cells). Furthermore, treatment with PSC 833 was associate d with upregulation of PAI-1 mRNA (similar to 3.5-fold) and immunoacti vity (similar to twofold) in the HB8065/R cells. Level of tissue inhib itor of metalloproteinases (TIMP)-1 was also significantly increased i n the HB8065/R cells compared to the HB8065/S cells, whereas both cell lines showed low constitutive expression of TIMP-2. Levels of TIMPs w ere not altered by PSC 833. These data suggest that overexpression of Pgp in these hepatoma cells may covariate with the phenotypes of both enhanced in vitro invasiveness and high PAI-1 expression, whether rand omly acquired or not.