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

Abstract

<div>Abstract<p>Germline mutations of <i>TP53</i>, 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 <i>p53</i> R172H knock-in mutation (<i>p53<sup>172H/H</sup></i>, homolog of the human <i>TP53</i> R175H LFS mutation) with myoglobin-knockout (<i>MB<sup>−/−</sup></i>) mice known to have decreased FAO. <i>MB<sup>−/−</sup> p53<sup>172H/H</sup></i> 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 <i>p53</i> R172H mutation promotes mitochondrial metabolism and ribosome biogenesis, both of which are suppressed by the disruption of <i>MB</i>. The activation of ribosomal protein S6, involved in protein translation and implicated in cancer promotion, was also inhibited in the absence of <i>MB</i>. To further confirm the role of FAO in lymphomagenesis, mitochondrial FAO enzyme, carnitine palmitoyltransferase 2 (CPT2), was specifically disrupted in T cells of <i>p53<sup>172H/H</sup></i> mice using a Cre-<i>lox</i>P–mediated strategy. The heterozygous knockout of <i>CPT2</i> resulted in thymus FAO haploinsufficiency and an approximately 30% improvement in survival time, paralleling the antiproliferative signaling observed with <i>MB</i> disruption. Thus, this study demonstrates that moderating FAO in LFS can suppress tumorigenesis and improve cancer-free survival with potential implications for cancer prevention.</p>Prevention Relevance:<p>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 <i>TP53</i>, dampens aberrant pro-tumorigenic cell signaling and improves the survival time of these mice, thereby revealing a potential strategy for cancer prevention in patients.</p></div>