INDUCTION OF MULTIDRUG-RESISTANCE DOWN-REGULATES THE EXPRESSION OF CFTR IN COLON EPITHELIAL-CELLS

The epithelial cell line HT-29, which constitutively expresses the cys tic fibrosis transmembrane conductance regulator (CFTR), was induced t o become drug resistant by cultivation in the presence of colchicine. The gradual acquisition of drug resistance was associated with a corre sponding increase in the expression of the multidrug resistance P-glyc oprotein (P-gp) and a marked (>80%) decrease in the constitutive level s of CTFR protein, as determined by immunoblotting. The reduction in C FTR content occurred at the onset of acquisition of drug resistance wh en P-gp expression was still relatively low. Reversal of drug resistan ce by removal of colchicine from the culture medium led to a 70% decre ase in P-gp levels and a concomitant 40% increase in CFTR. The levels of other membrane proteins such as Na+-K+-ATPase and alkaline phosphat ase remained relatively constant (<26% variation). We propose that a s elective downregulation of CFTR is elicited by acquisition of the mult idrug resistance (MDR) phenotype and that induction of P-gp expression leads to a reversible repression of CFTR biosynthesis. These findings provide an experimental foundation for the complementary patterns of expression of the CFTR and MDR1 genes observed in vivo.