title: The role of P-glycoprotein/cellular prion protein interaction in multidrug-resistant breast cancer cells treated with paclitaxel.
abstract: 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.
authors.affiliation: Department of Pathology, Shanghai Medical College, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032, China.
authors.forename: Q-Q
authors.initials: QQ
authors.lastname: Li
authors.forename: X-X
authors.initials: XX
authors.lastname: Cao
authors.forename: J-D
authors.initials: JD
authors.lastname: Xu
authors.forename: Q
authors.initials: Q
authors.lastname: Chen
authors.forename: W-J
authors.initials: WJ
authors.lastname: Wang
authors.forename: F
authors.initials: F
authors.lastname: Tang
authors.forename: Z-Q
authors.initials: ZQ
authors.lastname: Chen
authors.forename: X-P
authors.initials: XP
authors.lastname: Liu
authors.forename: Z-D
authors.initials: ZD
authors.lastname: Xu
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000590:Amino Acid Chloromethyl Ketones / Q000378:metabolism; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D017209:Apoptosis / Q000502:physiology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D021941:Caveolae / Q000378:metabolism; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor / Q000187:drug effects*; D015853:Cysteine Proteinase Inhibitors / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D017239:Paclitaxel / Q000494:pharmacology*; D018621:PrPC Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000590:Amino Acid Chloromethyl Ketones; D000972:Antineoplastic Agents, Phytogenic; D051242:Caveolin 1; D015853:Cysteine Proteinase Inhibitors; D018621:PrPC Proteins; C096713:benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone; D066246:ErbB Receptors; D017239:Paclitaxel