Search

Macrophages are particularly abundant and play an important role throughout the tumor progression process, namely, tumor‐associated macrophages (TAM) in the tumor microenvironment. TAM can be polarized to disparate functional phenotypes, the M1 and M2 macrophages. M1‐like type macrophages are defined as pro‐inflammatory cells involved in killing cancer cells, while M2‐like type cells can specially promote tumor growth and metastasis, tissue remodeling and immunosuppression. In this study, we first found that integrin β3 was highly expressed on the surface of TAM, both in vivo and in vitro, that displayed the M2‐like characteristics. Under intervention of CYC or triptolide, the integrin β3 inhibitors, the M2 polarization of TAM could be inhibited. Moreover, in the cell model of M2 polarization, either blockade or knockout/knockdown of integrin β3 could also suppress macrophage M2 polarization, which suggested that the M2 polarization was dependent on integrin β3. Using knockdown of peroxisome proliferator‐activated receptor‐γ (PPARγ), an M2 regulator, we found that expression and activation of PPARγ participated in M2 polarization that was mediated by integrin β3. Finally, to verify the activity of integrin β3 inhibitors on TAM in vivo, 4T1 tumor‐bearing mice were treated with CYC or triptolide; in response, the M1/M2 ratio of TAM was up‐regulated, while the infiltration of total lymphocytes into tumor tissue was not altered. In general, our study found a connection between integrin β3 and macrophage polarization, which provides a strategy for facilitating M2 to M1 repolarization and reconstructing the tumor immune microenvironment.

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.

// Yuxin Shu 1, * , Yan Lu 1, * , Xiaojuan Pang 1 , Wei Zheng 1 , Yahong Huang 1 , Jiahong Li 1 , Jianguo Ji 3, 4 , Can Zhang 2 , Pingping Shen 1 1 State Key Laboratory of Pharmaceutical Biotechnology and Model Animal Research Center (MARC), Nanjing University, Nanjing 210023, China 2 Center of Drug Discovery, State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, PR China 3 The State Key Laboratory of Protein and Plant Gene Research, College of Life Sciences, Peking University, Beijing 100871, China 4 Institute of System Biomedicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China * These authors contributed equally to this work Correspondence to: Pingping Shen, email: ppshen@nju.edu.cn Can Zhang, email: zhangcan@cpu.edu.cn Keywords: phosphorylation, PPARγ, PFKFB4, hepatocellular carcinoma, glycolysis Received: June 01, 2016 Accepted: October 14, 2016 Published: October 19, 2016 ABSTRACT Peroxisome proliferator-activating receptor γ (PPARγ), a transcription factor, is involved in many important biological processes, including cell terminal differentiation, survival and apoptosis. However, the role of PPARγ, which regulates tumour promoter and oncogene expression, is not well understood in hepatocellular carcinoma (HCC). In the present study, based on evidence from clinical samples that phosphorylation of PPARγ at Ser84 is up-regulated in human liver tumours, we confirmed that phosphorylation of PPARγ was also significantly increased in an HCC mouse model and was increased by Mitogen-activated protein kinase (MEK)/ Extracellular-signal-regulated kinases (ERK) kinase. Next, we performed an RNA microarray analysis, and our data indicated that dephosphorylation of PPARγ at Ser84 affects the expression of glycolysis-related genes and pro-proliferation genes, which supposedly promote proliferation of HCC cells. Using a chromatin immunoprecipitation (ChIP) assay, we demonstrated that the observed PPARγ-mediated induction of 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 4 (PFKFB4) expression was directly modulated by the transcriptional activity of its promoter. Furthermore, using knockdown of PFKFB4, we elucidated that the stimulation of PPARγ phosphorylation on glycolysis and proliferation in HCC is dependent on PFKFB4. Together, these findings extend our understanding of how liver tumour cells reprogram their glycolytic pathways by post-translational modification of specific transcription factors and lay a foundation for the screening of new targets for the treatment of HCC.

High-fat diets (HFDs) have been found to influence central nervous system development and to cause cognitive impairments in human epidemiologic studies, as well as in animal investigations. These adverse effects on learning and memory induced by an HFD have been associated with an impaired hippocampus, including hippocampal oxidative damage. Previously, we had found that α-lipoic acid (α-LA) could ameliorate the oxidative stress in non-neural organs (liver, jejunum, and spleen) induced by a 10-week HFD (21.2% fat) food regimen in mice. In this study, we investigated whether a 10-week HFD (21.2% fat) induced oxidative stress in the hippocampus or impaired spatial learning in mice and whether LA ameliorated these effects. The HFD was found to induce oxidative stress (a decrease in catalase activity, glutathione peroxidase activity, and total antioxidative capacity and an increase in malondialdehyde levels) in the mouse hippocampus. In addition, we found that the HFD impaired spatial recognition memory of mice in the Y-maze paradigm. Furthermore, the hippocampal oxidative stress and impaired spatial recognition memory of the mice were reduced in HFD diets supplemented with 0.1% LA. These findings suggest that LA, as a strong antioxidant, may help prevent HFD-induced learning impairments by ameliorating associated oxidative stress in the hippocampus.