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Suppression of gain-of-function mutant p53 with metabolic inhibitors reduces tumor growth in vivo.

ABSTRACT: Mutation of p53 occasionally results in a gain of function, which promotes tumor growth. We asked whether destabilizing the gain-of-function protein would kill tumor cells. Downregulation of the gene reduced cell proliferation in p53-mutant cells, but not in p53-null cells, indicating that the former depended on the mutant protein for survival. Moreover, phenformin and 2-deoxyglucose suppressed cell growth and simultaneously destabilized mutant p53. The AMPK pathway, MAPK pathway, chaperone proteins and ubiquitination all contributed to this process. Interestingly, phenformin and 2-deoxyglucose also reduced tumor growth in syngeneic mice harboring the p53 mutation. Thus, destabilizing mutant p53 protein in order to kill cells exhibiting "oncogene addiction" could be a promising strategy for combatting p53 mutant tumors.

SUBMITTER: Jung CL

PROVIDER: S-EPMC5363612 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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Suppression of gain-of-function mutant p53 with metabolic inhibitors reduces tumor growth in vivo.

Jung Chae Lim CL Mun Hyemin H Jo Se-Young SY Oh Ju-Hee JH Lee ChuHee C Choi Eun-Kyung EK Jang Se Jin SJ Suh Young-Ah YA

Oncotarget 20161101 47

Mutation of p53 occasionally results in a gain of function, which promotes tumor growth. We asked whether destabilizing the gain-of-function protein would kill tumor cells. Downregulation of the gene reduced cell proliferation in p53-mutant cells, but not in p53-null cells, indicating that the former depended on the mutant protein for survival. Moreover, phenformin and 2-deoxyglucose suppressed cell growth and simultaneously destabilized mutant p53. The AMPK pathway, MAPK pathway, chaperone prot ...[more]

PMID: 27765910

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