Ischemia-reperfusion-inducible protein modulates cell sensitivity to anticancer drugs by regulating activity of efflux transporter

Abstract

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.

Role of the Transporter Regulator Protein (RS1) in the Modulation of Concentrative Nucleoside Transporters (CNTs) in Epithelia

“…This inhibitory effect was also shown for related proteins belonging to the SLC22 gene family, such as OCT3 and organic anion transporter 1, and for unrelated transporters such as the dopamine, norepinephrine, and serotonin transporters (Jiang et al, 2005). IRIP was shown to modulate expression levels at the plasma membrane for the multidrug resistance transporter protein P-glycoprotein, thus modulating doxorubicin-induced cytotoxicity in HeLa cells (Prokopenko and Mirochnitchenko, 2009). Whether RS1 similarly modulates drug efflux remains to be established.…”

MicroRNA-125b-2 confers human glioblastoma stem cells resistance to temozolomide through the mitochondrial pathway of apoptosis

“…At present, cancer drug resistance is considered a multifactorial phenomenon involving several major mechanisms, such as a decreased uptake of water-soluble drugs, an increased repair of DNA damage, reduced apoptosis, altered metabolism of drugs, and an increased energy-dependent efflux of chemotherapeutic drugs that diminish the ability of cytotoxic agents to kill cancer cells (35). miRNA expression that affected multiple genes simultaneously provided support for this hypothesis (36).…”

Ischemia/Reperfusion-Inducible Protein Modulates the Function of Organic Cation Transporter 1 and Multidrug and Toxin Extrusion 1

“…IRIP has been previously reported to negatively regulate several transporter proteins in cell cultures 8, 9 . Here we at first sought to determine whether IRIP regulated the activities of human OCT1 and MATE1 as additional targets.…”

“…Although the exact details are subject to future intensive research, this may be reconciled by a feedback mechanism. The decreased expression of certain genes such as IRIP, which affect the expression of transporters at post-transcriptional levels such as reduced degradation by proteasome (e.g., P-glycoprotein 9 ), may increase functional transporter protein amounts. As such, by a feedback mechanism, less transporter gene transcripts are required to maintain the homeostatsis via the transporter proteins.…”