The Triterpenoid CDDO-Methyl Ester Redirects Macrophage Polarization and Reduces Lung Tumor Burden in a Nrf2-Dependent Manner.
The Triterpenoid CDDO-Methyl Ester Redirects Macrophage Polarization and Reduces Lung Tumor Burden in a Nrf2-Dependent Manner.
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DOI：
10.3390/antiox12010116
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发表时间：
2023-01-03
期刊：
影响因子：
7
通讯作者：
Liby, Karen T.
中科院分区：
文献类型：
--
作者：
Moerland, Jessica A.;Leal, Ana S.;Lockwood, Beth;Demireva, Elena Y.;Xie, Huirong;Krieger-Burke, Teresa;Liby, Karen T.
关键词：
NRF 2/KEAP 1通路保护健康细胞免于恶性转化并维持细胞内稳态。高达30%的人肺肿瘤获得组成型NRF 2活性，这有助于癌细胞存活和化疗耐药性，但肿瘤微环境中免疫细胞中NRF 2活化的影响尚未得到充分研究。巨噬细胞可以促进癌症的进展或消退，这取决于背景，NRF 2激活会影响巨噬细胞的活性。NRF 2激活剂CDDO-甲基酯（CDDO-Me或bardoxolone methyl）将Nrf 2野生型（WT）肿瘤诱导的骨髓源性巨噬细胞（TE-BMDM）从肿瘤促进表型重编程为肿瘤抑制表型，表现为M1标志物TNFα、IL-6和MHC-II增加以及肿瘤促进因子VEGF、CCL 2和CD 206减少。在Nrf 2敲除（KO）TE-BMDM中未观察到变化。CDDO-Me在WT但非Nrf 2 KO A/J小鼠中降低肿瘤负荷（p < 0.001）并改善病理分级（p < 0.05）。Nrf 2 KO小鼠的肿瘤负荷是WT小鼠的4.6倍（p < 0.001），与治疗无关。CDDO-Me增加了WT小鼠中肺浸润巨噬细胞的数量，但降低了这些细胞中的CD 206表达（p < 0.0001）。总之，Nrf 2 KO加剧了A/J小鼠的肺肿瘤发生，CDDO-Me促进了Nrf 2依赖性抗癌巨噬细胞表型。
The NRF2/KEAP1 pathway protects healthy cells from malignant transformation and maintains cellular homeostasis. Up to 30% of human lung tumors gain constitutive NRF2 activity which contributes to cancer cell survival and chemoresistance, but the effects of NRF2 activation in immune cells within the tumor microenvironment are underexplored. Macrophages can promote cancer progression or regression depending on context, and NRF2 activation affects macrophage activity. The NRF2 activator CDDO-Methyl ester (CDDO-Me or bardoxolone methyl) reprogrammed Nrf2 wild-type (WT) tumor-educated bone marrow-derived macrophages (TE-BMDMs) from a tumor-promoting to a tumor-inhibiting phenotype, marked by an increase in M1 markers TNFα, IL-6, and MHC-II and a decrease in the tumor-promoting factors VEGF, CCL2, and CD206. No changes were observed in Nrf2 knockout (KO) TE-BMDMs. CDDO-Me decreased tumor burden (p < 0.001) and improved pathological grade (p < 0.05) in WT but not Nrf2 KO A/J mice. Tumor burden in Nrf2 KO mice was 4.6-fold higher (p < 0.001) than in WT mice, irrespective of treatment. CDDO-Me increased the number of lung-infiltrating macrophages in WT mice but lowered CD206 expression in these cells (p < 0.0001). In summary, Nrf2 KO exacerbates lung tumorigenesis in A/J mice, and CDDO-Me promotes an Nrf2-dependent, anti-cancer macrophage phenotype.
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影响因子：
4.6
作者：
Hartmann W;Blankenhaus B;Brunn ML;Meiners J;Breloer M
通讯作者：
Breloer M
影响因子：
5.1
作者：
通讯作者：
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DOI：
10.1073/pnas.0500815102
发表时间：
2005-03-22
影响因子：
11.1
作者：
Dinkova-Kostova, AT;Liby, KT;Talalay, P
通讯作者：
Talalay, P
DOI：
10.1073/pnas.93.24.13943
发表时间：
1996-11-26
影响因子：
11.1
作者：
Chan, KM;Lu, RH;Kan, YW
通讯作者：
Kan, YW
影响因子：
12.4
作者：
Hsieh CH;Hsieh HC;Shih FS;Wang PW;Yang LX;Shieh DB;Wang YC
通讯作者：
Wang YC