Rlip depletion prevents spontaneous neoplasia in TP53 null mice

Sanjay Awasthi, Joshua Tompkins, Jyotsana Singhal, Arthur D. Riggs, Sushma Yadav, Xiwei Wu, Sharda Singh, Charles Warden, Zheng Liu, Jinhui Wang, Thomas P. Slavin, Jeffrey N. Weitzel, Yate Ching Yuan, Meenakshi Awasthi, Satish K. Srivastava, Yogesh C. Awasthi, Sharad S. Singhal

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

TP53 (p53) is a tumor suppressor whose functions are lost or altered in most malignancies. p53 homozygous knockout (p53/) mice uniformly die of spontaneous malignancy, typically T-cell lymphoma. RALBP1 (RLIP76, Rlip) is a stress-protective, mercapturic acid pathway transporter protein that also functions as a Ral effector involved in clathrin-dependent endocytosis. In stark contrast to p53/ mice, Rlip/ mice are highly resistant to carcinogenesis. We report here that partial Rlip deficiency induced by weekly administration of an Rlip-specific phosphorothioate antisense oligonucleotide, R508, strongly inhibited spontaneous as well as benzo(a)pyrene-induced carcinogenesis in p53/ mice. This treatment effectively prevented large-scale methylomic and transcriptomic abnormalities suggestive of inflammation found in cancer-bearing p53/ mice. The remarkable efficiency with which Rlip deficiency suppresses spontaneous malignancy in p53/ mice has not been observed with any previously reported pharmacologic or genetic intervention. These findings are supported by cross-breeding experiments demonstrating that hemizygous Rlip deficiency also reduces the spontaneous malignancy phenotype of p53+/ mice. Rlip is found on the cell surface, and antibodies directed against Rlip were found to inhibit growth and promote apoptosis of cell lines as effectively as Rlip siRNA. The work presented here investigates several features, including oxidative DNA damage of the Rlip-p53 association in malignant transformation, and offers a paradigm for the mechanisms of tumor suppression by p53 and the prospects of suppressing spontaneous malignancy in hereditary cancer syndromes such as Li-Fraumeni.

Original languageEnglish (US)
Pages (from-to)3918-3923
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number15
DOIs
StatePublished - Jan 1 2018

Keywords

  • Cancer prevention
  • Cancer signalling
  • Cytokine
  • RALBP1
  • TP53

ASJC Scopus subject areas

  • General

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  • Cite this

    Awasthi, S., Tompkins, J., Singhal, J., Riggs, A. D., Yadav, S., Wu, X., Singh, S., Warden, C., Liu, Z., Wang, J., Slavin, T. P., Weitzel, J. N., Yuan, Y. C., Awasthi, M., Srivastava, S. K., Awasthi, Y. C., & Singhal, S. S. (2018). Rlip depletion prevents spontaneous neoplasia in TP53 null mice. Proceedings of the National Academy of Sciences of the United States of America, 115(15), 3918-3923. https://doi.org/10.1073/pnas.1719586115