Cellular and Molecular Immunology Research Unit (CMIRU), Faculty of Allied Health Sciences, Naresuan University, Mueang, Phitsanulok, Thailand.
Department of Microbiology, Faculty of Medicine, Srinakharinwirot University, Bangkok, Thailand.
PeerJ. 2024 Sep 18;12:e18090. doi: 10.7717/peerj.18090. eCollection 2024.
Tumor-associated macrophages (TAMs) play a critical function in the development of tumors and are associated with protumor M2 phenotypes. Shifting TAMs towards antitumor M1 phenotypes holds promise for tumor immunotherapy. Oleamide, a primary fatty acid amide, has emerged as a potent anticancer and immunomodulatory compound. However, the regulatory effects of oleamide on TAM phenotypes remain unclear.
We used real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) and enzyme-linked immunosorbent assay (ELISA) techniques to study the influence of oleamide on primary human monocyte-derived TAM phenotypes, and we investigated the protein expression profiles based on mass spectrometry to analyze the effect of oleamide on macrophage polarization. Moreover, the advantageous binding scores between oleamide and these target candidate proteins are examined using molecular docking.
Our study revealed that oleamide effectively suppressed the M2-like TAM phenotype by reducing interleukin (IL)-10 production and downregulating M2-like markers, including vascular endothelial growth factor A (VEGFA), MYC proto-oncogene, bHLH transcription factor (c-Myc), and mannose receptor C-type 1 (CD206). Moreover, the conditioned medium derived from oleamide-treated TAMs induces apoptosis of MDA-MB-231 breast cancer cells. Proteomic analysis identified 20 candidate up- and down-regulation proteins targeted by oleamide, showing modulation activity associated with the promotion of the M1-like phenotype. Furthermore, molecular docking demonstrated favorable binding scores between oleamide and these candidate proteins. Collectively, our findings suggest that oleamide exerts a potent antitumor effect by promoting the antitumor M1-like TAM phenotype. These novel insights provide valuable resources for further investigations into oleamide and macrophage polarization which inhibit the progression of breast cancer, which may provide insight into immunotherapeutic approaches for cancer.
肿瘤相关巨噬细胞（TAMs）在肿瘤的发展中起着关键作用，与促肿瘤 M2 表型相关。将 TAMs 向抗肿瘤 M1 表型转变有望成为肿瘤免疫治疗的一种方法。油酸酰胺是一种主要的脂肪酸酰胺，已成为一种有效的抗癌和免疫调节化合物。然而，油酸酰胺对 TAM 表型的调节作用尚不清楚。
我们使用实时定量逆转录聚合酶链反应（qRT-PCR）和酶联免疫吸附测定（ELISA）技术研究油酸酰胺对原代人单核细胞衍生的 TAM 表型的影响，并通过质谱分析蛋白质表达谱来分析油酸酰胺对巨噬细胞极化的影响。此外，使用分子对接检查油酸酰胺与这些候选靶蛋白之间的有利结合评分。
我们的研究表明，油酸酰胺通过减少白细胞介素（IL）-10 的产生并下调 M2 样标志物，包括血管内皮生长因子 A（VEGFA）、原癌基因 MYC、碱性螺旋-环-螺旋转录因子（c-Myc）和甘露糖受体 C 型 1（CD206），有效地抑制了 M2 样 TAM 表型。此外，来自油酸酰胺处理的 TAMs 的条件培养基诱导 MDA-MB-231 乳腺癌细胞凋亡。蛋白质组学分析鉴定出 20 种候选上调和下调蛋白，这些蛋白被油酸酰胺靶向，显示出与促进 M1 样表型相关的调节活性。此外，分子对接表明油酸酰胺与这些候选蛋白之间具有良好的结合评分。总之，我们的研究结果表明，油酸酰胺通过促进抗肿瘤 M1 样 TAM 表型发挥强大的抗肿瘤作用。这些新的发现为进一步研究油酸酰胺和巨噬细胞极化提供了有价值的资源，从而抑制乳腺癌的进展，为癌症的免疫治疗方法提供了新的思路。
