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RLIP76 Is a Major Determinant of Radiation Sensitivity

¹ Department of Chemistry and Biochemistry and ² Office of Information Technology, University of Texas at Arlington; ³ Texas Cancer Center, Arlington, Texas; ⁴ Department of Radiation Oncology, Virginia Commonwealth University, Richmond, Virginia; Departments of ⁵ Pathology and ⁶ Human Biological Chemistry and Genetics, University of Texas Medical Branch at Galveston, Galveston, Texas; and ⁷ Lexicon Genetics, Inc., The Woodlands, Texas

Requests for reprints: Sanjay Awasthi, Department of Chemistry and Biochemistry, University of Texas at Arlington, Science Hall Room 223, 502 Yates Street, Arlington, TX 76019-0065. Phone: 817-272-5444; Fax: 817-272-3808; E-mail: sanjay.awasthi{at}usoncology.com.

RLIP76 (RALBP1) is a glutathione-conjugate transporter that is a critical component of clathrin-coated pit–mediated endocytosis, as well as in stress responses. In cultured cells, it provides protection from stressors including heat, oxidant chemicals, chemotherapeutic agents, UV irradiation, and X-irradiation. Here, we show marked reduction in glutathione conjugate transport capacity and stepwise increase in radiation sensitivity associated with heterozygous or homozygous loss of the RLIP76 gene in mice. Survival after radiation in homozygous knockout animals was significantly shorter than either the heterozygous knockouts or the wild type. Delivery of recombinant RLIP76 to mice lacking RLIP76 via a liposomal delivery system rescued radiation sensitivity. Furthermore, treatment of wild-type mice with RLIP76-containing liposomes conferred resistance to radiation. These findings suggest that inhibiting RLIP76 could be used for sensitization to radiation during cancer therapy and that RLIP76 liposomes could be radioprotective agents useful for treatment of iatrogenic or catastrophic radiation poisoning.

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