Baicalein Potentiated M1 Macrophage Polarization in Cancer Through Targeting PI3Kγ/ NF-κB Signaling.
Baicalein Potentiated M1 Macrophage Polarization in Cancer Through Targeting PI3Kγ/ NF-κB Signaling.
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DOI：
10.3389/fphar.2021.743837
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发表时间：
2021
影响因子：
5.6
通讯作者：
Wu J
中科院分区：
文献类型：
--
作者：
He S;Wang S;Liu S;Li Z;Liu X;Wu J
黄芩素是从黄芩中提取的生物活性成分之一。近年来研究表明黄芩素具有抗肿瘤作用，但其作用机制尚需进一步研究。在本研究中，我们发现黄芩素可以抑制乳腺癌和黑色素瘤小鼠模型中的肿瘤生长，并作为免疫调节剂促进肿瘤相关巨噬细胞（TAMs）的浸润并使TAMs向M1样表型倾斜。黄芩素还诱导THP-1衍生的巨噬细胞中的M1样表型极化。同时，经黄芩苷处理后，M1巨噬细胞相关促炎因子（包括TNF-α、IL-1β、CXCL 9和CXCL 10）的表达增加。从机制上讲，RNA-seq数据表明黄芩素通过NF-κB/TNF-α信号通路增强M1巨噬细胞极化。ELISA和共聚焦显微镜检测证实，黄芩素能显著诱导TNF-α的产生和NF-κB的激活，而TNF-α中和抑制黄芩素诱导的巨噬细胞向M1极化，NF-κB P65敲低抑制黄芩素诱导的THP-1源性巨噬细胞TNF-α的产生。据报道，磷酸肌醇3-激酶（PI 3 k）γ是巨噬细胞极化的关键分子，抑制PI 3 K γ会激活NF-κ B相关的炎症信号。通过药理网络分析，推测PI 3 K γ可能是黄芩素的主要作用靶点之一。对接程序和表面等离子体共振（SPR）结果证实黄芩素具有良好的PI 3 K γ结合活性。黄芩素不仅能直接抑制PI 3 K γ的蛋白激酶活性，而且能降低PI 3 K γ的mRNA和蛋白表达，提示黄芩素可能是一种新型的PI 3 K γ抑制剂。总之，黄芩素介导TAMs向M1-TAMs倾斜，然后抑制肿瘤生长。这些作用至少部分与PI 3 K γ/NF-κB信号通路有关。
Baicalein is one of the bioactive compounds extracted from Scutellaria baicalensis. Recent studies indicated the antitumor effects of baicalein, however, the underlying mechanisms are needed to be further determined. In this study, we found that baicalein could inhibit the tumor growth in mice models of breast cancer and melanoma and worked as an immunomodulator to promote the infiltration of tumor-associated macrophages (TAMs) and skew the TAMs towards the M1-like phenotype. Baicalein also induced M1-like phenotype polarization in THP-1-derived macrophages. Meanwhile, the expression of pro-inflammatory factors associated with M1 macrophages, including TNF-α, IL-1β, CXCL9 and CXCL10, were increased after baicalein treatment. Mechanistically, the RNA-seq data suggested that baicalein potentiated the M1 macrophage polarization via the NF-κB/TNF-α signaling pathway. ELISA and confocal microscopy assay confirmed that baicalein significantly induced the production of TNF-α and the activation of NF-κB, while TNF-α neutralization inhibited baicalein-induced macrophage polarization toward M1, and NF-κB P65 knock-down suppressed baicalein-induced TNF-α production in THP-1-derived macrophages. Phosphoinositide 3-kinase (PI3k) γ has been reported as a key molecule in macrophage polarization, and inhibition of PI3Kγ activates the NF-κB-related inflammatory signals. Our pharmacological network analysis predicted that PI3Kγ might be one of the major targets of baicalein. The results from the docking program and surface plasmon resonance (SPR) confirmed that baicalein displayed good binding activity to PI3Kγ. We further found that baicalein not only exhibited a direct inhibitory effect on the protein kinase activity of PI3Kγ, but also reduced the mRNA and protein expression of PI3Kγ, indicating that baicalein might be a novel PI3Kγ inhibitor. In summary, baicalein mediated the TAMs skewing to M1-TAMs, and then retarded tumor growth. These effects, at least in part, were linked to the PI3Kγ/NF-κB signaling.
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DOI：
10.1073/pnas.1720948115
发表时间：
2018-04-24
影响因子：
11.1
作者：
Peranzoni E;Lemoine J;Vimeux L;Feuillet V;Barrin S;Kantari-Mimoun C;Bercovici N;Guérin M;Biton J;Ouakrim H;Régnier F;Lupo A;Alifano M;Damotte D;Donnadieu E
通讯作者：
Donnadieu E
DOI：
10.1158/1078-0432.ccr-16-3122
发表时间：
2017-07-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Brown JM;Recht L;Strober S
通讯作者：
Strober S
影响因子：
64.8
作者：
De Henau O;Rausch M;Winkler D;Campesato LF;Liu C;Cymerman DH;Budhu S;Ghosh A;Pink M;Tchaicha J;Douglas M;Tibbitts T;Sharma S;Proctor J;Kosmider N;White K;Stern H;Soglia J;Adams J;Palombella VJ;McGovern K;Kutok JL;Wolchok JD;Merghoub T
通讯作者：
Merghoub T
DOI：
10.3390/molecules25235677
发表时间：
2020-12-02
期刊：
Molecules (Basel, Switzerland)
影响因子：
--
作者：
Nik Salleh NNH;Othman FA;Kamarudin NA;Tan SC
通讯作者：
Tan SC
影响因子：
10.9
作者：
Angela Aznar, M.;Planelles, Lourdes;Melero, Ignacio
通讯作者：
Melero, Ignacio