Diminished drug transport and augmented radiation sensitivity caused by loss of RLIP76

Sharad S. Singhal, Sushma Yadav, Jyotsana Singhal, Mukesh Sahu, Archana Sehrawat, Sanjay Awasthi

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)3408-3414
Number of pages7
JournalFEBS Letters
Volume582
Issue number23-24
DOIs
StatePublished - Oct 15 2008
Externally publishedYes

Keywords

  • Drug resistance
  • Embryonic fibroblasts
  • Glutathione conjugate
  • Ral-interacting protein
  • Transport

ASJC Scopus subject areas

  • Biophysics
  • Structural Biology
  • Biochemistry
  • Molecular Biology
  • Genetics
  • Cell Biology

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