Capase-1 cleaves PPARg for potentitating the pro-tumor action of TAMs

Tumor-associated macrophages (TAMs) 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 TAM differentiation remain largely unknown. Here, we report that caspase-1 promotes TAM differentiation by cleaving peroxisome proliferator-activated receptor gamma (PPARγ) at Asp64, thus generating a 41 kDa fragment. This truncated PPARγ 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 TAM differentiation. Furthermore, the administration of caspase-1 inhibitors or the infusion of bone marrow-derived macrophages (BMDMs) genetically engineered to overexpress murine MCAD markedly suppresses tumor growth. Therefore, targeting the caspase-1/PPARγ/MCAD pathway might be a promising therapeutic approach to prevent tumor progression. To further evaluate the effect of the caspase-1 inhibitor YVAD on TAM differentiation, we used a microarray platform to comprehensively analyze gene expression in THP-1 macrophages cocultured with MCF-7 cells in the presence or absence of YVAD and in THP-1 macrophages alone. We specifically selected genes associated with caspase-1 cleavage, with a particular emphasis on genes whose expression patterns changed after treatment with caspase-1 inhibitors, for example, genes up-regulated in the coculture group (Coculture vs Ctrl) but down-regulated upon administration of YVAD (YVAD vs Coculture), or vice versa.