OVEREXPRESSION OF THE CYSTIC-FIBROSIS TRANSMEMBRANE CONDUCTANCE REGULATOR IN NIH 3T3 CELLS LOWERS MEMBRANE-POTENTIAL AND INTRACELLULAR PH AND CONFERS A MULTIDRUG-RESISTANCE PHENOTYPE

Because of the similarities between the cystic fibrosis transmembrane conductance regulator (CFTR) and multidrug resistance (MDR) proteins, recent observations of decreased plasma membrane electrical potential (Delta Psi) in cells overexpressing either MDR protein or the CFTR, an d the effects of Delta Psi on passive diffusion of chemotherapeutic dr ugs, we have analyzed chemotherapeutic drug resistance for NIH 3T3 cel ls overexpressing different levels of functional CFTR. Three separate clones not previously exposed to chemotherapeutic drugs exhibit resist ance to doxorubicin, vincristine, and colchicine that is similar to MD R transfectants not previously exposed to chemotherapeutic drugs. Two other clones expressing lower levels of CFTR are less resistant. As sh own previously these clones exhibit decreased plasma membrane Delta Ps i similar to MDR transfectants, but four of five exhibit mildly acidif ied intracellular pH in contrast to MDR transfectants, which are in ge neral alkaline. Thus the MDR protein and CFTR-mediated MDR phenotypes are distinctly different. Selection of two separate CFTR clones on eit her doxorubicin or vincristine substantially increases the observed MD R and leads to increased CFTR (but not measurable MDR or MRP) mRNA exp ression. CFTR overexpressors also exhibit a decreased rate of H-3-vinb lastine uptake. These data reveal a new and previously unrecognized co nsequence of CFTR expression, and are consistent with the hypothesis t hat membrane depolarization is an important determinant of tumor cell MDR.