Nature communications, 2017-10, Vol.8 (1), p.766-18, Article 766
2017
Details
- Autor(en) / Beteiligte
- Titel
- Caspase-1 cleaves PPARγ for potentiating the pro-tumor action of TAMs
- Ist Teil von
- Nature communications, 2017-10, Vol.8 (1), p.766-18, Article 766
- Ort / Verlag
- England: Nature Publishing Group
- Erscheinungsjahr
- 2017
- Link zum Volltext
- Quelle
- Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals
- Beschreibungen/Notizen
- 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 (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 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/PPARγ/MCAD pathway might be a promising therapeutic approach to prevent tumor progression.Tumor associated macrophages (TAMs) promote cancer progression. Here, the author show that caspase-1 promotes TAMs differentiation by attenuating medium-chain acyl-CoA dehydrogenase activity and that inhibition of this axis results in suppression of tumour growth in a transgenic mouse model of breast cancer.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2041-1723eISSN: 2041-1723DOI: 10.1038/s41467-017-00523-6Titel-ID: cdi_doaj_primary_oai_doaj_org_article_9b1dfe9c6f8041e2a2d8b1d09e428ffc
- Format
- –
- Schlagworte
- Acyl-CoA dehydrogenase, Acyl-CoA Dehydrogenase - genetics, Acyl-CoA Dehydrogenase - metabolism, Animals, Bone marrow, Breast cancer, Cancer, Caspase, Caspase 1 - metabolism, Caspase Inhibitors - pharmacology, Caspase-1, Cell Differentiation - immunology, Chains, Dehydrogenase, Dehydrogenases, Differentiation, Energy Metabolism, Fatty acids, Fatty Acids - metabolism, Female, Genetic engineering, Humans, Lipid Metabolism, Macrophages, Macrophages - drug effects, Macrophages - immunology, MCF-7 Cells, Metastases, Mice, Mice, Nude, Mitochondria, Mitochondria - metabolism, Neoplasms - immunology, Neoplasms - metabolism, Oxidation, PPAR gamma - metabolism, Regulatory mechanisms (biology), THP-1 Cells, Transgenic mice, Tumor Microenvironment - immunology, Tumors