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.

• Authors: Chae Lim Jung, Hyemin Mun, Se-Young Jo, Ju-Hee Oh, ChuHee Lee, Eun-Kyung Choi, Se Jin Jang, Young-Ah Suh
• Journal: Oncotarget (Oncotarget) Vol. 7 Issue 47 Pg. 77664-77682 (Nov 22 2016) ISSN: 1949-2553 [Electronic] United States
• PMID: 27765910 (Publication Type: Journal Article)

Chemical References

• Tumor Suppressor Protein p53
• Deoxyglucose
• Phenformin

Topics

• A549 Cells
• Animals
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Deoxyglucose (administration & dosage, pharmacology)
• Gene Expression Regulation, Neoplastic (drug effects)
• Gene Knock-In Techniques
• Humans
• MAP Kinase Signaling System (drug effects)
• Mice
• Mutation
• Neoplasm Metastasis
• Neoplasms (pathology)
• Phenformin (administration & dosage, pharmacology)
• Tumor Suppressor Protein p53 (genetics)
• Xenograft Model Antitumor Assays