Inhibiting mitochondrial respiration prevents cancer in a mouse model of Li-Fraumeni syndrome
Ping-yuan Wang, … , Antonio Tito Fojo, Paul M. Hwang
Ping-yuan Wang, … , Antonio Tito Fojo, Paul M. Hwang
Published November 21, 2016
Citation Information: J Clin Invest. 2017;127(1):132-136. https://doi.org/10.1172/JCI88668.
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Brief Report Oncology

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

Ping-yuan Wang, Jie Li, Farzana L. Walcott, Ju-Gyeong Kang, Matthew F. Starost, S. Lalith Talagala, Jie Zhuang, Ji-Hoon Park, Rebecca D. Huffstutler, Christina M. Bryla, Phuong L. Mai, Michael Pollak, Christina M. Annunziata, Sharon A. Savage, Antonio Tito Fojo, Paul M. Hwang

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Figure 3

Metformin inhibits mitochondria and activates antiproliferation signaling in LFS patients.

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Metformin inhibits mitochondria and activates antiproliferation signalin...
(A) Effect of metformin on OCR and OCR/ECAR ratio of LFS patient blood MNCs (n = 13–14). (B) Representative immunoblots of MNCs from 2 out of 6 examined patients. (C) Effect of metformin treatment on PCr recovery time constant (Tc) after exercise in patient skeletal muscle. (D) Mitochondrial inhibition counteracts tumor-promoting activities of mutant p53 (dotted lines). Statistical differences by 1-way ANOVA (A) and Wilcoxon matched-pairs signed rank test (C). *P < 0.01.