Regulation of volume-sensitive Cl- channels in multi-drug resistant MCF7 cells.
The P-glycoprotein (P-gp) is thought to be involved in the regulation of volume-sensitive chloride channels. In this study, the possible coupling between P-gp and swelling-activated chloride channels has been examined in MCF7 cells with sensitive (MDR-), resistant (MDR+), and reversed resistant (MDR(REV)) phenotypes. Western blot analysis showed that incubation of cells with doxorubicin induced P-gp expression in a reversible manner. Exposure of MDR+ cells to hypotonicity resulted in an inhibition of P-gp activity while hypotonic challenges induced swelling-activated chloride currents (I(Cl-swell)) in MDR-, MDR+, and MDR(REV) MCF7 cells. While verapamil inhibited I(Cl-swell) in all cell types, doxorubicin and vincristine rapidly and reversibly inhibited I(Cl-swell) uniquely in MDR+. Intracellular dialysis of MDR+ cells with C219 anti-P-gp antibody abolished the sensitivity of I(Cl-swell) to doxorubicin and led to a response pattern very close to that of MDR- cells. Taken together, these results strongly suggest that the P-glycoprotein regulates I(Cl-swell) in resistant MCF7.
Marin
Matthieu
M
Laboratory of Ecotoxicology UPRES-EA 3222, IFRMP 23, University of Le Havre, 25 rue Philippe Lebon, 76058 Le Havre cedex, France. matthieu.marin@univ-lehavre.fr
Poret
Agnès
A
Maillet
Géraldine
G
Leboulenger
François
F
Le Foll
Frank
F
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D048429:Cell Size; D018118:Chloride Channels / Q000378:metabolism*; D018432:Drug Resistance, Multiple; D006801:Humans; D015640:Ion Channel Gating; D014882:Water-Electrolyte Balance
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018118:Chloride Channels