title: Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome.
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.
authors.forename: Ping-Yuan
authors.initials: PY
authors.lastname: Wang
authors.forename: Jie
authors.initials: J
authors.lastname: Li
authors.forename: Farzana L
authors.initials: FL
authors.lastname: Walcott
authors.forename: Ju-Gyeong
authors.initials: JG
authors.lastname: Kang
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Starost
authors.forename: S Lalith
authors.initials: SL
authors.lastname: Talagala
authors.forename: Jie
authors.initials: J
authors.lastname: Zhuang
authors.forename: Ji-Hoon
authors.initials: JH
authors.lastname: Park
authors.forename: Rebecca D
authors.initials: RD
authors.lastname: Huffstutler
authors.forename: Christina M
authors.initials: CM
authors.lastname: Bryla
authors.forename: Phuong L
authors.initials: PL
authors.lastname: Mai
authors.forename: Michael
authors.initials: M
authors.lastname: Pollak
authors.forename: Christina M
authors.initials: CM
authors.lastname: Annunziata
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Savage
authors.forename: Antonio Tito
authors.initials: AT
authors.lastname: Fojo
authors.forename: Paul M
authors.initials: PM
authors.lastname: Hwang
mesh_terms: D000328:Adult; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D005260:Female; D006801:Humans; D019169:Jurkat Cells; D016864:Li-Fraumeni Syndrome / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008817:Mice, Mutant Strains; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D010101:Oxygen Consumption / Q000187:drug effects* / Q000235:genetics; D010865:Pilot Projects; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D008687:Metformin