Biophysical Journal 69: 883-895 (1995)
© 1995 the Biophysical Society

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Wei, L Y Articles by Roepe, P D Search for Related Content PubMed PubMed Citation Articles by Wei, L Y Articles by Roepe, P D

Overexpression of the cystic fibrosis transmembrane conductance regulator in NIH 3T3 cells lowers membrane potential and intracellular pH and confers a multidrug resistance phenotype.

Program in Molecular Pharmacology and Therapeutics, Memorial Sloan-Kettering Cancer Center, New York, New York 10021, USA.

ABSTRACT

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, and the effects of delta psi on passive diffusion of chemotherapeutic drugs, we have analyzed chemotherapeutic drug resistance for NIH 3T3 cells overexpressing different levels of functional CFTR. Three separate clones not previously exposed to chemotherapeutic drugs exhibit resistance to doxorubicin, vincristine, and colchicine that is similar to MDR transfectants not previously exposed to chemotherapeutic drugs. Two other clones expressing lower levels of CFTR are less resistant. As shown previously these clones exhibit decreased plasma membrane delta psi similar to MDR transfectants, but four of five exhibit mildly acidified intracellular pH in contrast to MDR transfectants, which are in general alkaline. Thus the MDR protein and CFTR-mediated MDR phenotypes are distinctly different. Selection of two separate CFTR clones on either doxorubicin or vincristine substantially increases the observed MDR and leads to increased CFTR (but not measurable MDR or MRP) mRNA expression. CFTR overexpressors also exhibit a decreased rate of 3H -vinblastine uptake. These data reveal a new and previously unrecognized consequence of CFTR expression, and are consistent with the hypothesis that membrane depolarization is an important determinant of tumor cell MDR.

This article has been cited by other articles:

				F. Thévenod, J.-P. Hildebrandt, Jör. Striessnig, H. R. de Jonge, and I. Schulz Chloride and Potassium Conductances of Mouse Pancreatic Zymogen Granules Are Inversely Regulated by a approx80-kDa mdr1a Gene Product J. Biol. Chem., February 9, 1996; 271(6): 3300 - 3305. [Abstract] [Full Text] [PDF]

				G. D. Luker, T. P. Flagg, Q. Sha, K. E. Luker, C. M. Pica, C. G. Nichols, and D. Piwnica-Worms MDR1 P-glycoprotein Reduces Influx of Substrates without Affecting Membrane Potential J. Biol. Chem., December 21, 2001; 276(52): 49053 - 49060. [Abstract] [Full Text] [PDF]