The role of P-glycoprotein/cellular prion protein interaction in multidrug-resistant breast cancer cells treated with paclitaxel.
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.
Li
Q-Q
QQ
Department of Pathology, Shanghai Medical College, Fudan University, 138 Yi Xue Yuan Road, Shanghai 200032, China.
Cao
X-X
XX
Xu
J-D
JD
Chen
Q
Q
Wang
W-J
WJ
Tang
F
F
Chen
Z-Q
ZQ
Liu
X-P
XP
Xu
Z-D
ZD
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*
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