Oncotarget

Research Papers:

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

Chae Lim Jung, Hyemin Mun, Se-Young Jo, Ju-Hee Oh, ChuHee Lee, Eun-Kyung Choi, Se Jin Jang and Young-Ah Suh _

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Oncotarget. 2016; 7:77664-77682. https://doi.org/10.18632/oncotarget.12758

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Abstract

Chae Lim Jung1,, Hyemin Mun1,, Se-Young Jo1, Ju-Hee Oh1, ChuHee Lee4, Eun-Kyung Choi1,2, Se Jin Jang1,3, Young-Ah Suh1

1Institute for Innovative Cancer Research, Asan Institute for Life Science, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea

2Department of Medicinal Oncology, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea

3Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Republic of Korea

4Department of Biochemistry and Molecular Biology, School of Medicine, Yeungnam University, Daegu 42415, Republic of Korea

Co-first authors: C. L. Jung and H. Mun contributed equally to this work

Correspondence to:

Young-Ah Suh, email: ysuh@amc.seoul.kr

Se Jin Jang, email: jangsejin@amc.seoul.kr

Keywords: p53 mutant knock-in mouse, gain-of-function mutation, cancer metabolism, oncogene addiction, AMPK signaling

Received: January 11, 2016    Accepted: September 26, 2016    Published: October 19, 2016

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.


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