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Cancer Prevention Research
Cancer Prevention Research
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Research Article

Reducing Fatty Acid Oxidation Improves Cancer-free Survival in a Mouse Model of Li-Fraumeni Syndrome

Ping-Yuan Wang, Jin Ma, Jie Li, Matthew F. Starost, Michael J. Wolfgang, Komudi Singh, Mehdi Pirooznia, Ju-Gyeong Kang and Paul M. Hwang
Ping-Yuan Wang
1Cardiovascular Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
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Jin Ma
1Cardiovascular Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
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Jie Li
1Cardiovascular Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
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Matthew F. Starost
2Division of Veterinary Resources, NIH, Bethesda, Maryland.
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Michael J. Wolfgang
3Department of Biological Chemistry, Johns Hopkins University School of Medicine, Baltimore, Maryland.
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Komudi Singh
4Bioinformatics and Computational Biology, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
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Mehdi Pirooznia
4Bioinformatics and Computational Biology, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
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  • ORCID record for Mehdi Pirooznia
Ju-Gyeong Kang
1Cardiovascular Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
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Paul M. Hwang
1Cardiovascular Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Maryland.
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  • ORCID record for Paul M. Hwang
  • For correspondence: hwangp@mail.nih.gov
DOI: 10.1158/1940-6207.CAPR-20-0368 Published January 2021
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Abstract

Germline mutations of TP53, which cause the cancer predisposition disorder Li-Fraumeni syndrome (LFS), can increase mitochondrial activity as well as fatty acid β-oxidation (FAO) in mice. Increased fatty acid metabolism can promote cancer malignancy, but its specific contribution to tumorigenesis in LFS remains unclear. To investigate this, we crossed LFS mice carrying the p53 R172H knock-in mutation (p53172H/H, homolog of the human TP53 R175H LFS mutation) with myoglobin-knockout (MB−/−) mice known to have decreased FAO. MB−/− p53172H/H double-mutant mice also showed mildly reduced FAO in thymus, a common site of T lymphoma development in LFS mice, in association with an approximately 40% improvement in cancer-free survival time. RNA sequencing profiling revealed that the p53 R172H mutation promotes mitochondrial metabolism and ribosome biogenesis, both of which are suppressed by the disruption of MB. The activation of ribosomal protein S6, involved in protein translation and implicated in cancer promotion, was also inhibited in the absence of MB. To further confirm the role of FAO in lymphomagenesis, mitochondrial FAO enzyme, carnitine palmitoyltransferase 2 (CPT2), was specifically disrupted in T cells of p53172H/H mice using a Cre-loxP–mediated strategy. The heterozygous knockout of CPT2 resulted in thymus FAO haploinsufficiency and an approximately 30% improvement in survival time, paralleling the antiproliferative signaling observed with MB disruption. Thus, this study demonstrates that moderating FAO in LFS can suppress tumorigenesis and improve cancer-free survival with potential implications for cancer prevention.

Prevention Relevance: Mildly inhibiting the increased fatty acid oxidation observed in a mouse model of Li-Fraumeni syndrome, a cancer predisposition disorder caused by inherited mutations of TP53, dampens aberrant pro-tumorigenic cell signaling and improves the survival time of these mice, thereby revealing a potential strategy for cancer prevention in patients.

Footnotes

  • Note: Supplementary data for this article are available at Cancer Prevention Research Online (http://cancerprevres.aacrjournals.org/).

  • Cancer Prev Res 2021;14:31–40

  • Received July 8, 2020.
  • Revision received August 11, 2020.
  • Accepted September 15, 2020.
  • Published first September 21, 2020.
  • ©2020 American Association for Cancer Research.
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Cancer Prevention Research: 14 (1)
January 2021
Volume 14, Issue 1
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Reducing Fatty Acid Oxidation Improves Cancer-free Survival in a Mouse Model of Li-Fraumeni Syndrome
Ping-Yuan Wang, Jin Ma, Jie Li, Matthew F. Starost, Michael J. Wolfgang, Komudi Singh, Mehdi Pirooznia, Ju-Gyeong Kang and Paul M. Hwang
Cancer Prev Res January 1 2021 (14) (1) 31-40; DOI: 10.1158/1940-6207.CAPR-20-0368

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Reducing Fatty Acid Oxidation Improves Cancer-free Survival in a Mouse Model of Li-Fraumeni Syndrome
Ping-Yuan Wang, Jin Ma, Jie Li, Matthew F. Starost, Michael J. Wolfgang, Komudi Singh, Mehdi Pirooznia, Ju-Gyeong Kang and Paul M. Hwang
Cancer Prev Res January 1 2021 (14) (1) 31-40; DOI: 10.1158/1940-6207.CAPR-20-0368
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