EXPERIMENTALLY-INDUCED CHANGES IN THE ENDOCYTIC TRAFFIC OF P-GLYCOPROTEIN ALTER DRUG-RESISTANCE OF CANCER-CELLS

The MDR-1 gene product, plasma membrane glycoprotein or P-glycoprotein (PGP), has been shown to confer drug resistance to cancer cells by ac ting as an energy-dependent drug-efflux pump. We have examined the end ocytic traffic of PGP in human multidrug-resistant cells and tested wh ether the traffic and the steady-state intracellular localization of P GP can be experimentally modulated. Here we show that 1) under steady state similar to 70% of cellular PGP is on the surface whereas similar to 30% is intracellular, 2) surface PGP undergoes constitutive endocy tosis and recycling, 3) endocytosis of PGP involves clathrin and adapt in complex 2-dependent mechanism, and 4) PGP cycles through a Rab5-res ponsive endosomal compartment. Biochemical (such as antibody crosslink ing of PGP or treatment of cells with chloroquine) and molecular (such as overexpression of Rab5) treatments were used to modulate the endoc ytic/recycling traffic of PGP. Such treatments resulted in the redistr ibution of PGP from the cell surface to intracellular compartments. Ce lls with such ''mislocalized'' PGP showed a decrease in multidrug resi stance, suggesting that clinically relevant strategies can be attempte d by modulating PGP's temporal and spatial distribution within cancer cells.