Experimentally induced changes in the endocytic traffic of P-glycoprotein alter drug resistance of cancer cells.

Academic Article

Abstract

  • The MDR-1 gene product, plasma membrane glycoprotein or P-glycoprotein (PGP), has been shown to confer drug resistance to cancer cells by acting as an energy-dependent drug-efflux pump. We have examined the endocytic traffic of PGP in human multidrug-resistant cells and tested whether the traffic and the steady-state intracellular localization of PGP can be experimentally modulated. Here we show that 1) under steady state approximately 70% of cellular PGP is on the surface whereas approximately 30% is intracellular, 2) surface PGP undergoes constitutive endocytosis and recycling, 3) endocytosis of PGP involves clathrin and adaptin complex 2-dependent mechanism, and 4) PGP cycles through a Rab5-responsive endosomal compartment. Biochemical (such as antibody crosslinking of PGP or treatment of cells with chloroquine) and molecular (such as overexpression of Rab5) treatments were used to modulate the endocytic/ recycling traffic of PGP. Such treatments resulted in the redistribution of PGP from the cell surface to intracellular compartments. Cells with such "mislocalized" PGP showed a decrease in multidrug resistance, suggesting that clinically relevant strategies can be attempted by modulating PGP's temporal and spatial distribution within cancer cells.
  • Published In

    Keywords

  • ATP Binding Cassette Transporter, Subfamily B, Member 1, Adaptor Protein Complex alpha Subunits, Adaptor Proteins, Vesicular Transport, Antibodies, Carcinoma, Cell Membrane, Chloroquine, Clathrin, Cross-Linking Reagents, Drug Resistance, Multiple, Endocytosis, Endosomes, GTP-Binding Proteins, Humans, Intestinal Neoplasms, Intracellular Membranes, Membrane Proteins, Tumor Cells, Cultured, rab5 GTP-Binding Proteins
  • Digital Object Identifier (doi)

    Author List

  • Kim H; Barroso M; Samanta R; Greenberger L; Sztul E
  • Start Page

  • C687
  • End Page

  • C702
  • Volume

  • 273
  • Issue

  • 2 Pt 1