Ischemia-reperfusion-inducible protein modulates cell sensitivity to anticancer drugs by regulating activity of efflux transporter.
Human ischemia-reperfusion-inducible protein (hIRIP) or hYrdC belongs to the SUA5/YrdC/YciO protein family and affects activity of a variety of cellular transporters. We observed that overexpression of wild-type or dominant-negative mutant of hIRIP protein affects the cellular sensitivity to anticancer drugs with different mechanisms of toxicity. Here we investigated in detail the effect of hIRIP on cell sensitivity to doxorubicin and show that hIRIP inhibits the drug efflux. Multidrug-resistant P-glycoprotein was identified as one of the target transporters. IRIP does not influence P-glycoprotein biosynthesis but affects its processing and promotes degradation. We also show that P-glycoprotein is associated with COP-alpha, one of the proteins of the COPI complex. This interaction is sensitive to the level of hIRIP expression. These findings suggest that hIRIP expression can regulate cargo assembly and function of efflux transporters, including P-glycoprotein, which mediates one of the most common mechanisms of the multidrug resistance.
Prokopenko
Olga
O
Department of Biochemistry, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Mirochnitchenko
Oleg
O
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000903:Antibiotics, Antineoplastic / Q000493:pharmacokinetics / Q000633:toxicity; D000972:Antineoplastic Agents, Phytogenic / Q000493:pharmacokinetics / Q000633:toxicity; D017209:Apoptosis / Q000187:drug effects; D001120:Arginine / Q000378:metabolism; D002166:Camptothecin / Q000493:pharmacokinetics / Q000633:toxicity; D020755:Coat Protein Complex I / Q000378:metabolism; D004317:Doxorubicin / Q000493:pharmacokinetics / Q000633:toxicity; D018432:Drug Resistance, Multiple / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D007668:Kidney / Q000166:cytology; D008969:Molecular Sequence Data; D021382:Protein Sorting Signals / Q000187:drug effects / Q000235:genetics; D021381:Protein Transport / Q000187:drug effects; D016601:RNA-Binding Proteins / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D054875:Ubiquitination / Q000187:drug effects
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D020755:Coat Protein Complex I; D021382:Protein Sorting Signals; D016601:RNA-Binding Proteins; D004317:Doxorubicin; D001120:Arginine; D019204:GTP-Binding Proteins; C478762:YRDC protein, human; D002166:Camptothecin