title: Dietary downregulation of mutant p53 levels via glucose restriction: mechanisms and implications for tumor therapy.
abstract: The majority of human tumors express mutant forms of p53 at high levels, promoting gain of oncogenic functions and correlating with disease progression, resistance to therapy and unfavorable prognosis. p53 mutant accumulation in tumors is attributed to the ability to evade degradation by the proteasome, the only currently recognized machinery for p53 disruption. We report here that glucose restriction (GR) induces p53 mutant deacetylation, routing it for degradation via autophagy. Depletion of p53 leads, in turn, to robust autophagic activation and to cell death, while expression of degradation-defective mutant p53 blocks autophagy and enables survival to GR. Furthermore, we found that a carbohydrate-free dietetic regimen that lowers the fasting glucose levels blunts p53 mutant expression and oncogenic activity relative to a normal diet in several animal model systems. These findings indicate that the stability of mutant forms of p53 is influenced by the levels of glucose and by dietetic habits. They also unravel the existence of an inhibitory loop between autophagy and mutant p53 that can be exploited therapeutically.
authors.affiliation: Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC USA.
authors.forename: Olga Catalina
authors.initials: OC
authors.lastname: Rodriguez
authors.forename: Sujatra
authors.initials: S
authors.lastname: Choudhury
authors.forename: Vamsi
authors.initials: V
authors.lastname: Kolukula
authors.forename: Eveline E
authors.initials: EE
authors.lastname: Vietsch
authors.forename: Jason
authors.initials: J
authors.lastname: Catania
authors.forename: Anju
authors.initials: A
authors.lastname: Preet
authors.forename: Katherine
authors.initials: K
authors.lastname: Reynoso
authors.forename: Jill
authors.initials: J
authors.lastname: Bargonetti
authors.forename: Anton
authors.initials: A
authors.lastname: Wellstein
authors.forename: Chris
authors.initials: C
authors.lastname: Albanese
authors.forename: Maria Laura
authors.initials: ML
authors.lastname: Avantaggiati
mesh_terms: D000818:Animals; D001343:Autophagy; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D050528:Diet, Carbohydrate-Restricted; D015536:Down-Regulation; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000378:metabolism; D014183:Transplantation, Heterologous; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2; D046988:Proteasome Endopeptidase Complex