Abstract 3690: Metabolic regulation of mutant p53 stability by the mevalonate pathway

Abstract

Abstract Introduction: Mutations in the p53 gene are mostly missense mutations and result in accumulation of dysfunctional p53 protein in tumors with oncogenic gain-of-function activities. Increasing evidence indicates that stabilization of mutant p53 (mutp53) in tumors is crucial for its oncogenic activities including tumor progression and drug resistance, while downregulation of mutp53 reduces oncogenicity of cancer cells. These observations suggest that malignant properties of cancer cells are dependent on the presence of mutp53, thus providing a rationale to identify compounds that deplete mutant p53 with little impact on wild-type p53. Experimental procedures: Toward this goal, we performed high throughput screens of chemical libraries (∼9,000 compounds) with Saos2 (p53 null) cells expressing a fusion protein of p53R175H and luciferase, using luciferase as a reporter. Summary of data: This screening led us to identify “statins”, a class of cholesterol-lowering medications, as compounds that induced degradation of p53R175H. We found that other inhibitors of the mevalonate pathway, such as 6-fluoromevalonate and zoledronic acid, failed to induce p53R175H degradation, while statin-mediated inhibition of HMG-CoA reductase and subsequent reduction in mevalonte-5-phosphate triggered p53R175H degradation. These results suggest that statin's effect on p53R175H is specific and independent of protein prenylation/lipidation or cholesterol synthesis. Moreover, nuclear export of p53R175H was required for the statin-mediated degradation, which was mediated through an E3 ubiquitin ligase CHIP, but not MDM2. Interestingly, statins induced degradation of mainly conformational p53 mutants with minimal effects on the levels of wild-type p53 and DNA contact mutants. Conclusions: This is the first study demonstrating that mutp53 stability is regulated through a specific process of the mevalonate pathway, thereby providing a novel regulatory mechanism of mutp53 degradation. Our findings suggest that p53 mutation status in tumors may have an impact on efficacy of statins in cancer therapy. Citation Format: Tomoo Iwakuma, Atul Ranjan, Swathi V. Iyer, Subhash Padhye, Scott Weir, Anuradha Roy. Metabolic regulation of mutant p53 stability by the mevalonate pathway. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3690.