TY - JOUR
T1 - Diminished drug transport and augmented radiation sensitivity caused by loss of RLIP76
AU - Singhal, Sharad S.
AU - Yadav, Sushma
AU - Singhal, Jyotsana
AU - Sahu, Mukesh
AU - Sehrawat, Archana
AU - Awasthi, Sanjay
N1 - Funding Information:
This work was supported in part by National Institutes of Health Grants CA 77495 and CA 104661, Cancer Research Foundation of North Texas, Institute for Cancer Research and the Joe and Jessie Crump Fund for Medical Education.
PY - 2008/10/15
Y1 - 2008/10/15
N2 - This study was undertaken to characterize the consequences of Ral-interacting protein (RLIP76)-loss with respect to drug resistance, transport, radiation resistance, and alternative transport mechanisms in mouse embryonic fibroblasts (MEFs). MEFs were derived from RLIP76+/+, RLIP76+/- and RLIP76-/- mice. The transport of doxorubicin (DOX), colchicine (COL), leukotriene C4 and dinitrophenyl S-glutathione (DNP-SG) was analyzed in inside-out vesicles (IOVs) prepared from MEFs. We used immuno-titration of transport activity to determine the contribution of RLIP76, MRP1, and p-glycoprotein (Pgp) towards total transport activity. Loss of RLIP76 alleles resulted in significant sensitization to radiation, DOX, cisplatin, and vinorelbine (VRL). In IOVs prepared from MEFs, we observed a stepwise loss of transport activity. Loss of RLIP76 confers sensitivity to xenobiotics and radiation due to the loss of a common transport mechanism for glutathione-electrophile conjugates and xenobiotics.
AB - This study was undertaken to characterize the consequences of Ral-interacting protein (RLIP76)-loss with respect to drug resistance, transport, radiation resistance, and alternative transport mechanisms in mouse embryonic fibroblasts (MEFs). MEFs were derived from RLIP76+/+, RLIP76+/- and RLIP76-/- mice. The transport of doxorubicin (DOX), colchicine (COL), leukotriene C4 and dinitrophenyl S-glutathione (DNP-SG) was analyzed in inside-out vesicles (IOVs) prepared from MEFs. We used immuno-titration of transport activity to determine the contribution of RLIP76, MRP1, and p-glycoprotein (Pgp) towards total transport activity. Loss of RLIP76 alleles resulted in significant sensitization to radiation, DOX, cisplatin, and vinorelbine (VRL). In IOVs prepared from MEFs, we observed a stepwise loss of transport activity. Loss of RLIP76 confers sensitivity to xenobiotics and radiation due to the loss of a common transport mechanism for glutathione-electrophile conjugates and xenobiotics.
KW - Drug resistance
KW - Embryonic fibroblasts
KW - Glutathione conjugate
KW - Ral-interacting protein
KW - Transport
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U2 - 10.1016/j.febslet.2008.09.001
DO - 10.1016/j.febslet.2008.09.001
M3 - Article
C2 - 18789326
AN - SCOPUS:53049101724
SN - 0014-5793
VL - 582
SP - 3408
EP - 3414
JO - FEBS Letters
JF - FEBS Letters
IS - 23-24
ER -