Caspase-1 cleaves PPARγ for potentiating the pro-tumor action of TAMs

• DOI: 10.1038/s41467-017-00523-6
• Publication Date: 2017-09-27T09:33:19Z
• Authors: Zhiyuan Niu; Qian Shi; Wenlong Zhang; Yuxin Shu; Nanfei Yang; Bing Chen; Qingsong Wang; Xuyang Zhao; Jiajia Chen; Nan Cheng; Xiujing Feng; Zichun Hua; Jianguo Ji; Pingping Shen
• Keywords: Tumor progression

Abstract Tumor-associated macrophages are increasingly viewed as a target of great relevance in the tumor microenvironment, because their important role cancer progression and metastasis. However, endogenous regulatory mechanisms underlying tumor-associated macrophage differentiation remain largely unknown. Here, we report that caspase-1 promotes by cleaving peroxisome proliferator-activated receptor gamma (PPARγ) at Asp64, thus generating 41 kDa fragment. This truncated PPARγ translocates to mitochondria, where it directly interacts with medium-chain acyl-CoA dehydrogenase (MCAD). binding event attenuates MCAD activity inhibits fatty acid oxidation, thereby leading accumulation lipid droplets promoting differentiation. Furthermore, administration inhibitors or infusion bone marrow-derived genetically engineered overexpress murine markedly suppresses growth. Therefore, targeting caspase-1/PPARγ/MCAD pathway might be promising therapeutic approach prevent progression.