Journal
NATURE COMMUNICATIONS
Volume 8, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-017-00523-6
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Funding
- National Natural Science Foundation of China [81273527, 81421091, 81473220, 81673439, 91013015]
- National Key Research and Development Program of China [2017YFA0205400]
- JDRF advanced postdoc fellowship award, USA [3-APF-2016-205-A-N]
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Tumor-associated macrophages are increasingly viewed as a target of great relevance in the tumor microenvironment, because of their important role in cancer progression and metastasis. However, the endogenous regulatory mechanisms underlying tumor-associated macrophage differentiation remain largely unknown. Here, we report that caspase-1 promotes tumor-associated macrophage differentiation by cleaving peroxisome proliferator-activated receptor gamma (PPAR gamma) at Asp64, thus generating a 41 kDa fragment. This truncated PPAR gamma translocates to mitochondria, where it directly interacts with medium-chain acyl-CoA dehydrogenase (MCAD). This binding event attenuates MCAD activity and inhibits fatty acid oxidation, thereby leading to the accumulation of lipid droplets and promoting tumor-associated macrophage differentiation. Furthermore, the administration of caspase-1 inhibitors or the infusion of bone marrow-derived macrophages genetically engineered to overexpress murine MCAD markedly suppresses tumor growth. Therefore, targeting the caspase-1/PPAR gamma/MCAD pathway might be a promising therapeutic approach to prevent tumor progression.
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