The role of P-glycoprotein/cellular prion protein interaction in multidrug-resistant breast cancer cells treated with paclitaxel

Cell Mol Life Sci. 2009 Feb;66(3):504-15. doi: 10.1007/s00018-008-8548-6.


We previously reported that treatment with P-glycoprotein (P-gp) substrates promotes in vitro invasion in multidrug-resistant (MDR) breast cancer cells. This effect is initiated by the P-gp pump function and mediated by interaction of P-gp with some unknown component(s). However, the underlying mechanism(s) remains poorly understood. Here we confirm a novel physical interaction between P-gp and cellular prion protein (PrP(c)). Blocking P-gp activity or depletion of PrP(c) inhibited paclitaxel (P-gp substrate)- induced invasion. Paclitaxel further facilitated the formation of P-gp/PrP(c) clusters residing in caveolar domains and promoted the association of P-gp with caveolin-1. Both caveolin-1 and the integrity of caveolae were required for the drug-induced invasion. In addition, the P-gp/PrP(c) complex also played an important role in anti-apoptotic activity of MCF7/Adr cells.These data provide new insights into the mode by which MDR breast cancers evade cytotoxic attacks from P-gp substrates and also suggest a role for P-gp/ PrP(c) interaction in this process.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / genetics
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism*
  • Amino Acid Chloromethyl Ketones / metabolism
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Apoptosis / physiology
  • Breast Neoplasms / metabolism*
  • Breast Neoplasms / pathology
  • Caveolae / metabolism
  • Caveolin 1 / genetics
  • Caveolin 1 / metabolism
  • Cell Line, Tumor / drug effects*
  • Cysteine Proteinase Inhibitors / metabolism
  • Drug Resistance, Neoplasm*
  • ErbB Receptors / genetics
  • ErbB Receptors / metabolism
  • Female
  • Humans
  • Paclitaxel / pharmacology*
  • PrPC Proteins / genetics
  • PrPC Proteins / metabolism*


  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Amino Acid Chloromethyl Ketones
  • Antineoplastic Agents, Phytogenic
  • Caveolin 1
  • Cysteine Proteinase Inhibitors
  • PrPC Proteins
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • ErbB Receptors
  • Paclitaxel