RLIP76 is a major determinant of radiation sensitivity
Open accessPublished version of a preprint
Abstract
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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Several lines of evidence support a key role for Rlip in detoxification of 4-HNE and response to oxidative stress.
“Several lines of evidence support a key role for Rlip in the detoxification of 4-HNE and response to oxidative stress [14,64,65], and thus the downregulation or degradation of Rlip may increase the damage caused by the elevated ROS emission resulting from amyloid β and mitochondrial dysfunction.”
From Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease? (2022) · cites this paper as [65]
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Hindle, A., Singh, S. P., Pradeepkiran, J. A., Bose, C., Vijayan, M., Kshirsagar, S., Sawant, N. A., & Reddy, P. H. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23116098 · Cited by 14 · see citing works
- Authors
- Awasthi, S., Singhal, S. S., Yadav, S., Singhal, J., Drake, K., Nadkar, A., Zajac, E., Wickramarachchi, D., Rowe, N., Yacoub, A., Boor, P., Dwivedi, S., Dent, P., Jarman, W. E., John, B., & Awasthi, Y. C.
- Affiliations
- 1Department of Chemistry and Biochemistry and
- The University of Texas at Arlington (US)
- Virginia Commonwealth University (US)
- 5Pathology and
- 7Lexicon Genetics, Inc., The Woodlands, Texas
- 3Texas Cancer Center, Arlington, Texas;
- 6Human Biological Chemistry and Genetics, University of Texas Medical Branch at Galveston, Galveston, Texas; and
- Venue
- Cancer Research
- Published
- 2005-07-15
- Volume
- 65
- Issue
- 14
- Pages
- 6022-6028
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2152130273
- Cited by
- 88
- References
- 0
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 1 · 2023: 3 · 2022: 4 · 2021: 8 · 2020: 3 · 2019: 4 · 2018: 4 · 2017: 4 · 2016: 2 · 2015: 5 · 2014: 3 · 2013: 4 · 2012: 4
- FWCI
- 5.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Public Health Service
- National Cancer Institute (CA 88906, CA 77495, R01CA088906, R01CA072995, CA72995, R01CA104661, R01CA077495, CA104661)
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 52825, R01DK052825)
- National Institute of Environmental Health Sciences (ES012171, R01ES012171)
- Topics
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Radiation Therapy and Dosimetry
- Keywords
- RLIP76, RALBP1, glutathione conjugate transport, radiosensitivity, radioresistance (biology), knockout mice, liposomal drug delivery, radioprotective agents, endocytosis, stress response, radiation toxicity
- MeSH terms
- Animals, Female, Glutathione, Humans, Immunohistochemistry, Liposomes, Male, Mice, Inbred C57BL, Radiation Tolerance, Mice, Knockout, ATP-Binding Cassette Transporters, GTPase-Activating Proteins, Mice
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