Abstract 4833: Glucose restriction induces degradation of p53 mutants via a selective autophagy-mediated pathway
Authors: Rodriguez Olga Catalina , Kokula Vamsi , Catania Jason , Preet Anju , Arshed, Arslaan , Pishvaian Michael , Albanese Christopher , Avantaggiati Maria L. 
Published: February 2011

Introduction. More than 50% of human tumors harbor missense mutations of the p53 gene product. In its wild-type conformation p53 is degraded via the proteasome, mainly through the action of the MDM2 E3 ubiquitin ligase. Unlike the wild-type protein, mutant forms of p53 accumulate at high levels and elude proteolysis, in part due to an altered modality of interaction with MDM2. High levels of p53 mutants in tumors appear to correlate with resistance to radio- and chemo-therapy, and are proposed to promote tumor progression. Furthermore, therapeutic interventions aimed at reducing p53 mutant levels have shown anti-tumor activity in vitro and in vivo. The mechanisms that regulate the stability of wild-type p53 are well understood during the DNA damage response. However, p53 can also be stabilized during adaptive metabolic stress conditions, such as during glucose deprivation. The goal of this work was to determine the effects of glucose availability on the oncogenic activity of mutant p53.

Methods. We investigated the effects of glucose availability in tumor cells expressing p53 mutants, in transgenic animals harboring p53 mutant alleles, and in xenograft models of breast cancer. The read-outs of these experiments were p53 stability, cellular proliferation and response to therapeutic agents.

Results. We found that p53 mutant protein levels are exquisitely sensitive to glucose availability: high glucose levels stabilize p53 mutants, while glucose restriction (GR) leads to their MDM2- and proteasome-independent degradation. This degradation requires instead the participation of the autophagic machinery and of the autophagic protein Beclin-1, which forms a complex with p53 in GR-treated cells. Importantly, in breast cancer cell lines GR alone does not lead to a net increase in autophagic flux, thus differing from autophagy activated during serum- or amino acid- depletion. Rather, GR uses the autophagic machinery to degrade selective targets, such as mutant p53. We further show that tumor cells where p53 mutant levels are lower due to GR, have reduced proliferation potential compared to tumors expressing native p53, and can be easily chemo-sensitized, significantly reducing the IC50 of all drugs examined. We then asked whether dietary restriction of glucose affects p53 mutant stability in living organisms. Preliminary results indicate that p53 mutant levels are higher in tissues of animals fed with high glucose-diet, relative to animals fed with a low glucose diet. We are currently investigating whether this change in p53 levels affects proliferation rates.

Conclusions. We propose that GR uses the autophagic machinery to induce degradation of oncogenic mutant p53, and thus interrupts their proliferative signals. Our findings further imply that dietary restriction of glucose would keep p53 mutant activity in check. Finally, GR overcomes the well-known chemo-resistance conveyed by p53 mutations.

Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4833.