K. Bjornland et al., HUMAN HEPATOMA-CELLS RICH IN P-GLYCOPROTEIN DISPLAY ENHANCED IN-VITROINVASIVE PROPERTIES COMPARED TO P-GLYCOPROTEIN-POOR HEPATOMA-CELLS, Oncology research, 10(5), 1998, pp. 255-262
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.