Niu Zhiyuan, Shi Qian, Zhang Wenlong, Shu Yuxin, Yang Nanfei, Chen Bing, Wang Qingsong, Zhao Xuyang, Chen Jiajia, Cheng Nan, Feng Xiujing, Hua Zichun, Ji Jianguo, Shen Pingping
State Key Laboratory of Pharmaceutical Biotechnology and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, 210023, China.
Department of Cellular and Integrative Physiology, The University of Texas Health Science Center at San Antonio, STRF-Greehey North Campus, 8403 Floyd Curl Drive, San Antonio, Texas, 78229-3904, USA.
Nat Commun. 2017 Oct 3;8(1):766. doi: 10.1038/s41467-017-00523-6.
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.
肿瘤相关巨噬细胞越来越被视为肿瘤微环境中一个极具相关性的靶点，因为它们在癌症进展和转移中发挥着重要作用。然而，肿瘤相关巨噬细胞分化的内源性调控机制在很大程度上仍不清楚。在此，我们报告半胱天冬酶-1通过在天冬氨酸64位切割过氧化物酶体增殖物激活受体γ（PPARγ）来促进肿瘤相关巨噬细胞分化，从而产生一个41 kDa的片段。这种截短的PPARγ易位至线粒体，在那里它直接与中链酰基辅酶A脱氢酶（MCAD）相互作用。这种结合事件减弱了MCAD的活性并抑制脂肪酸氧化，从而导致脂滴积累并促进肿瘤相关巨噬细胞分化。此外，给予半胱天冬酶-1抑制剂或输注经基因工程改造以过表达小鼠MCAD的骨髓来源巨噬细胞可显著抑制肿瘤生长。因此，靶向半胱天冬酶-1/PPARγ/MCAD途径可能是一种有前景的预防肿瘤进展的治疗方法。肿瘤相关巨噬细胞（TAMs）促进癌症进展。在此，作者表明半胱天冬酶-1通过减弱中链酰基辅酶A脱氢酶活性来促进TAMs分化，并且在乳腺癌转基因小鼠模型中抑制该轴会导致肿瘤生长受到抑制。
