title: 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.affiliation: Institute for Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
authors.forename: Chae Lim
authors.initials: CL
authors.lastname: Jung
authors.affiliation: Institute for Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
authors.forename: Hyemin
authors.initials: H
authors.lastname: Mun
authors.affiliation: Institute for Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
authors.forename: Se-Young
authors.initials: SY
authors.lastname: Jo
authors.affiliation: Institute for Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
authors.forename: Ju-Hee
authors.initials: JH
authors.lastname: Oh
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, Yeungnam University, Daegu 42415, Republic of Korea.
authors.forename: ChuHee
authors.initials: C
authors.lastname: Lee
authors.affiliation: Institute for Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.|Department of Medicinal Oncology, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
authors.forename: Eun-Kyung
authors.initials: EK
authors.lastname: Choi
authors.affiliation: Institute for Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.|Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
authors.forename: Se Jin
authors.initials: SJ
authors.lastname: Jang
authors.affiliation: Institute for Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea.
authors.forename: Young-Ah
authors.initials: YA
authors.lastname: Suh
mesh_terms: D000072283:A549 Cells; D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003847:Deoxyglucose / Q000008:administration & dosage* / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055879:Gene Knock-In Techniques; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D009154:Mutation; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000473:pathology*; D010629:Phenformin / Q000008:administration & dosage* / Q000494:pharmacology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D016159:Tumor Suppressor Protein p53; D003847:Deoxyglucose; D010629:Phenformin
keywords: AMPK signaling; cancer metabolism; gain-of-function mutation; oncogene addiction; p53 mutant knock-in mouse