Influence of exogenous RAR alpha gene on MDR1 expression and P-glycoprotein function in human and rodent cell lines

The goal of our study was to obtain direct evidence of co-ordinated regulat ion of P-glycoprotein (P-gp)-mediated multidrug resistance (MDR) and differ entiation in tumour cells and to study some signalling pathways involved in joint regulation of these two cell phenotypes. The sublines of human melan oma (mS) and hepatoma (human HepG2 and rat McA RH 7777) cell lines were obt ained by retroviral infection of the wild-type cells with the cDNA of the h uman retinoic acid receptor alpha (RAR alpha). The resulting sublines stabl y overexpressed exogenous RAR alpha gene. The infectants became more differ entiated than the parental cells as determined by a decrease in the synthes is of the embryo-specific alpha-fetoprotein in HepG2 and McA RH 7777 hepato ma cells and by an increase in melanin synthesis in mS cells. The different iation of human cells was accompanied by an increase in the amounts of MDR1 mRNA but not by an increase in P-gp activity as a drug transporter, in con trast, in the rat RARa overexpressing cells P-gp functional activity was el evated. Treatment with cytotoxic drug (colchicine) or retinoic acid (RA) re sulted in a slight increase in P-gp activity in the parental and RAR alpha- infected melanoma cells, whereas the increase in P-gp function in the infec ted hepatoma cells (both human and rat) was very prominent. Thus, we provid e new evidence that cell differentiation caused by the overexpression of th e gene participating in the differentiation programme leads to overexpressi on of MDR1 gene and drug resistance and that this effect is tissue and spec ies specific. These data imply that the activation of the RA-controlled sig nalling pathway up-regulates MDR1 gene expression.