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 January 3, 2017; First published November 21, 2016
Citation Information: J Clin Invest. 2017;127(1):132-136. https://doi.org/10.1172/JCI88668.
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Categories: 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 1

Genetic disruption of mitochondria reverses aberrant proliferation signaling and increases survival of p53172H/H mice.

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Genetic disruption of mitochondria reverses aberrant proliferation signa...
(A) OCRs of approximately 10-week-old mouse thymus cells (n = 5–7) and lactate in tail blood (average age approximately 12 weeks) (n = 14–19). (B) Upper panel shows Kaplan-Meier survival plot of p53172H/H control (n = 70), Polg+/mut p53172H/H (n = 34), and Polgmut/mut p53172H/H (n = 32) mice. Lower panel shows correlation between blood lactate level and survival time of Polg+/mut p53172H/H (r = 0.6, P = 0.057, n = 11) and Polgmut/mut p53172H/H (r = 0.7, P < 0.01, n = 18) mice. *P < 0.05; **P < 0.01; ***P < 0.001. (C) lmmunoblots of approximately 10-week-old p53+/+ and p53172H/H thymus tissues. Asterisks (lanes 7–9) indicate enlarged thymus samples with lymphoma. (D) Primary human myoblasts transduced with empty vector (–) or human p53 R175H cDNA (+) were serum starved for 3 hours prior to immunoblotting. (E) lmmunoblots of thymus and spleen samples obtained from age-matched Polg+/+ and Polg+/mut mice in p53172H/H background (lane 1, approximately 10 weeks old; lane 2, approximately 20 weeks old). Statistical differences by 1-way ANOVA (A), log-rank test (B, upper), and Pearson correlation coefficient test (B, lower).