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Cited by 25Drug Transport and Resistance MechanismsNeuroblastoma Research and TreatmentsCancer-related Molecular Pathways

Targeting p53-null neuroblastomas through RLIP76

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Singhal, Jyotsana, Yadav, Sushma, Nagaprashantha, Lokesh Dalasanur, Vatsyayan, Rit, Singhal, Sharad S., Awasthi, Sanjay·2011·Cancer Prevention Research
DOI 10.1158/1940-6207.capr-11-0025PMC PMC3107925
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Abstract

The search for p53-independent mechanism of cancer cell killing is highly relevant to pediatric neuroblastomas, where successful therapy is limited by its transformation into p53-mutant and a highly drug-resistant neoplasm. Our studies on the drug-resistant p53-mutant as compared with drug-resistant p53 wild-type neuroblastoma revealed a novel mechanism for resistance to apoptosis: a direct role of p53 in regulating the cellular concentration of proapoptotic alkenals by functioning as a specific and saturable allosteric inhibitor of the alkenal–glutathione conjugate transporter, RLIP76. The RLIP76-p53 complex was showed by both immunoprecipitation analyses of purified proteins and immunofluorescence analysis. Drug transport studies revealed that p53 inhibited both basal and PKCα-stimulated transport of glutathione conjugates of 4HNE (GSHNE) and doxorubicin. Drug resistance was significantly greater for p53-mutant as compared with p53 wild-type neuroblastoma cell lines, but both were susceptible to depletion of RLIP76 by antisense alone. In addition, inhibition of RLIP76 significantly enhanced the cytotoxicity of cisplatin. Taken together, these studies provide powerful evidence for a novel mechanism for drug and apoptosis resistance in p53-mutant neuroblastoma, based on a model of regulation of p53-induced apoptosis by RLIP76, where p53 is a saturable and specific allosteric inhibitor of RLIP76, and p53 loss results in overexpression of RLIP76; thus, in the absence of p53, the drug and glutathione-conjugate transport activities of RLIP76 are enhanced. Most importantly, our findings strongly indicate RLIP76 as a novel target for therapy of drug-resistant and p53-mutant neuroblastoma. Cancer Prev Res; 4(6); 879–89. ©2011 AACR.

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  • Rlip shows stress-responsive changes in activity and binds to p53 and HSF1.

    “Rlip shows stress-responsive changes in activity [31] and has been found to bind to the master stress-response transcription factors p53 and HSF1 (heat shock factor 1) [31,35].”

    From Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease? (2022) · cites this paper as [35]

    The Results section reports that RLIP76 binds p53. The Discussion describes stress-responsive changes in RLIP76 expression, rather than directly demonstrating changes in its activity, and says HSF-1 inhibits RLIP76 without stating that the two bind. The copy provides no page numbers for these passages. (LLM, conf=0.86)

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  • p53 binds to membrane Rlip, inhibiting transport of glutathione-conjugated 4-HNE and doxorubicin.

    “It has also been shown that p53 binds to membrane Rlip, inhibiting the transport of glutathione-conjugated 4-hydroxynonenal (4-HNE) and doxorubicin [35].”

    From Rlip76: An Unexplored Player in Neurodegeneration and Alzheimer’s Disease? (2022) · cites this paper as [35]

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Research works printed but not linked: 50

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Cited by

Sorted by citations

Authors
Singhal, J., Yadav, S., Nagaprashantha, L. D., Vatsyayan, R., Singhal, S. S., & Awasthi, S.
Affiliations
University of North Texas Health Science Center (US)
Corresponding author
Awasthi, Sanjay
ORCID
Venue
Cancer Prevention Research
Publisher
American Association for Cancer Research (AACR)
Published
2011-06-01
Volume
4
Issue
6
Pages
879-889
ISSN
  • 1940-6207 (ISSN-L)
  • 1940-6215
DOI
10.1158/1940-6207.capr-11-0025
PMC
PMC3107925
OpenAlex
W2124895836
Cited by
25
References
0
Citations by year
2026: 1 · 2024: 1 · 2022: 3 · 2021: 3 · 2020: 2 · 2019: 2 · 2018: 1 · 2017: 3 · 2015: 3 · 2013: 2 · 2012: 2
FWCI
0.74
Type
journal article
Language
en
Open access
Locations
  • Cancer Prevention Research (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • University of North Texas
  • National Institutes of Health
  • National Cancer Institute (CA 77495, R01CA077495)
Topics
  • Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
  • Health Sciences › Medicine › Neurology › Neuroblastoma Research and Treatments
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Keywords
neuroblastoma, TP53 mutation, RLIP76, apoptosis resistance, drug resistance, 4-hydroxynonenal, glutathione conjugates, doxorubicin, cisplatin, protein kinase C alpha, allosteric inhibition, childhood cancer treatment
MeSH terms
Animals, Antineoplastic Combined Chemotherapy Protocols, Child, Cisplatin, Cross-Linking Reagents, Doxorubicin, Glutathione, Humans, Immunoenzyme Techniques, Male, Mice, Nude, Neuroblastoma, Tumor Cells, Cultured, Blotting, Western, Tumor Suppressor Protein p53, Oligonucleotides, Antisense, Drug Resistance, Multiple, ATP-Binding Cassette Transporters, Drug Resistance, Neoplasm, GTPase-Activating Proteins, Immunoprecipitation, Mice

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