1. Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome.
- Author
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Wang PY, Li J, Walcott FL, Kang JG, Starost MF, Talagala SL, Zhuang J, Park JH, Huffstutler RD, Bryla CM, Mai PL, Pollak M, Annunziata CM, Savage SA, Fojo AT, and Hwang PM
- Subjects
- Adult, Animals, Cell Proliferation drug effects, Cell Proliferation genetics, Female, Humans, Jurkat Cells, Li-Fraumeni Syndrome genetics, Li-Fraumeni Syndrome metabolism, Male, Mice, Mice, Mutant Strains, Middle Aged, Mitochondria genetics, Mitochondria pathology, Neoplasms, Experimental genetics, Neoplasms, Experimental metabolism, Oxygen Consumption genetics, Pilot Projects, Signal Transduction drug effects, Signal Transduction genetics, Tumor Suppressor Protein p53 genetics, Tumor Suppressor Protein p53 metabolism, Li-Fraumeni Syndrome prevention & control, Metformin pharmacology, Mitochondria metabolism, Neoplasms, Experimental prevention & control, Oxygen Consumption drug effects
- Abstract
Li-Fraumeni syndrome (LFS) is a cancer predisposition disorder caused by germline mutations in TP53 that can lead to increased mitochondrial metabolism in patients. However, the implications of altered mitochondrial function for tumorigenesis in LFS are unclear. Here, we have reported that genetic or pharmacologic disruption of mitochondrial respiration improves cancer-free survival in a mouse model of LFS that expresses mutant p53. Mechanistically, inhibition of mitochondrial function increased autophagy and decreased the aberrant proliferation signaling caused by mutant p53. In a pilot study, LFS patients treated with metformin exhibited decreases in mitochondrial activity concomitant with activation of antiproliferation signaling, thus reproducing the effects of disrupting mitochondrial function observed in LFS mice. These observations indicate that a commonly prescribed diabetic medicine can restrain mitochondrial metabolism and tumorigenesis in an LFS model, supporting its further consideration for cancer prevention in LFS patients., Competing Interests: The authors have declared that no conflict of interest exists.
- Published
- 2017
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