Submitted on December 30, 2008
Revised on February 24, 2009
Accepted on March 9, 2009
Ischemia-Reperfusion Inducible Protein Modulates Cell Sensitivity to Anticancer Drugs by Regulating Activity of Efflux Transporter
olga prokopenko1 and oleg mirochnitchenko1*
1 UMDNJ
* To whom correspondence should be addressed. E-mail: mirochol{at}umdnj.edu.
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 anti-cancer drugs with different mechanisms of toxicity. Here we investigated in detail the effect of doxorubicin on cell sensitivity and show that hIRIP inhibits the drug efflux. Multidrug resistance 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
, one of the proteins of 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.
