Abstract 5244: Partial knockdown of RLIP76 prevents cancer susceptibility of p53 null mice

Abstract

Abstract P53 is a stress-responsive, genome protective, tumor suppressor whose functions are lost or altered in nearly all neoplasia. P53 homozygous knockout mice (p53-/-) develop spontaneous lymphoma and other malignancies in nearly 100% of cases by 6 months of life. In stark contrast, homozygous gene knockout of the stress-responsive, anti-apoptotic, mercapturic acid pathway transporter protein, RLIP76, results in marked protection from chemical carcinogenesis. P53 expression and activation is regulated by intermediary metabolites of this pathway, and p53 regulates the expression of key enzymes of this pathway. P53 can directly bind to RLIP76 through a CDK-interaction domain, and inhibit its transport activity as well as endocytosis stimulatory activity. These results indicate that RLIP76 is an effector of p53 in a manner analogous to its known function as the first known effector of the Ral pathways that regulate membrane plasticity, motility and invasion. This translates into reduced kinase signaling down-stream of membrane-receptor/ligand interactions. An inverse relationship between RLIP76 and p53 protein and mRNA expression has been observed in-vitro, and is confirmed by analysis of human cancer genomic analyses in the COH database. RLIP76 depletion causes apoptosis in cancer cells independent of p53 status, strengthening the view that RLIP76 is key down-stream effector of p53. We reasoned that if RLIP76 is necessary for cancer to develop in p53-deficient animals, its suppression will reduce the incidence of malignancy in 12-week old p53-/- mice treated with COHSA007 phosphorothioated antisense, 200 μg i.p.q.2wk till age 8 months. Results of our studies confirmed these predictions, since 4/4 scrambled antisense treated p53-/- mice developed T-cell lymphoma whereas 8/8 COHSA007 treated p53-/- mice survived to the end of the experiment without development of any malignancy. These findings demonstrate that RLIP76 is required for malignancy in the p53-/- mice. Taken in context of our previous studies showing that RLIP76-/- mice are highly resistant to inflammation and carcinogenesis in chemical carcinogenesis models of the skin and lung, the present findings strongly support the idea of an existential role of RLIP76 in the malignant phenotype, and strengthen the rationale for using targeted systemic depletion of RLIP76 for treatment of human neoplasia (Supported in part by the Department of Defense grant (W81XWH-16-1-0641) and USPHS grant CA 77495). Citation Format: Sharad S. Singhal, Jyotsana Singhal, Joshua Tompkins, David Horne, Xiwei Wu, Arthur Riggs, Sanjay Awasthi. Partial knockdown of RLIP76 prevents cancer susceptibility of p53 null mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5244. doi:10.1158/1538-7445.AM2017-5244