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- Title
Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome.
- Authors
Ping-yuan Wang; Jie Li; Walcott, Farzana L.; Ju-Gyeong Kang; Starost, Matthew F.; Talagala, Lalith; Jie Zhuang; ji-Hoon Park; Huffstutler, Rebecca D.; Bryla, Christina M.; Mai, Phuong L.; Pollak, Michael; Annunziata, Christina M.; Savage, Sharon A.; Fojo, Antonio Tito; Hwang, Paul M.; Wang, Ping-Yuan; Li, Jie; Kang, Ju-Gyeong; Talagala, S Lalith
- 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.
- Subjects
CANCER prevention; LI-Fraumeni syndrome; MITOCHONDRIAL physiology; GENETIC mutation; LABORATORY mice; MITOCHONDRIAL pathology; PROTEIN metabolism; TUMOR prevention; ANIMAL experimentation; CELL physiology; CELLULAR signal transduction; MICE; MITOCHONDRIA; PROTEINS; RESEARCH funding; TUMORS; PILOT projects; OXYGEN consumption; METFORMIN; PHARMACODYNAMICS; PREVENTION
- Publication
Journal of Clinical Investigation, 2017, Vol 127, Issue 1, p132
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI88668