Selenium modifies the osteoblast inflammatory stress response to bone metastatic breast cancer
Selenium modifies the osteoblast inflammatory stress response to bone metastatic breast cancer
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DOI：
10.1093/carcin/bgp227
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发表时间：
2009-11-01
期刊：
影响因子：
4.7
通讯作者：
Mastro, Andrea M.
中科院分区：
文献类型：
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作者：
Chen, Yu-Chi;Sosnoski, Donna M.;Mastro, Andrea M.
乳腺癌经常转移到骨骼，由于破骨细胞激活导致骨退化。转移瘤还会下调成骨细胞的分化和骨重建功能。此外，癌细胞引发成骨细胞炎症应激反应。人乳腺癌细胞（MDA-MB-231）条件培养基刺激成骨细胞（MC3T3-E1）表达的促炎介质，如白细胞介素(IL)-6、单核细胞化学引诱蛋白-1 （MCP-1）、环氧化酶-2 （COX-2）和诱导型一氧化氮合酶（iNOS），是破骨细胞活化和转移的关键。考虑到这些基因是由核因子- κ B (nf - κ B)，一种氧化还原敏感的转录因子调控的，我们假设硒（Se）可以通过调节nf - κ B来消除转移性乳腺癌细胞的炎症反应，咖啡酸苯乙酯和parthenolide可以抑制nf - κ B的激活，这是通过凝胶转移试验和核组分中p65的免疫印迹观察到的，同时也可以减少IL-6和MCP-1的产生。在MDA-MB-231条件培养基中，MC3T3-E1中添加甲基硒酸（MSA） （0.5 μ M ~ 4 μ M）可降低NF-kappa B的活化，导致IL-6、MCP-1、COX-2和iNOS的减少。在成骨细胞中添加MSA仅15分钟就能抑制NF-kappa B的激活，这表明可能涉及到短寿命的活性代谢物。然而，短暂暴露于MSA也会增加硒蛋白谷胱甘肽过氧化物酶1。总之，我们的数据表明，成骨细胞对转移性乳腺癌细胞的反应受NF-kappa B激活的调节，而NF-kappa B可以通过短寿命活性代谢物和/或硒蛋白被MSA有效抑制。因此，硒补充剂可以预防成骨细胞的炎症反应或抑制乳腺癌细胞、成骨细胞和破骨细胞相互作用时建立的恶性循环。
Breast cancer frequently metastasizes to the skeleton resulting in bone degradation due to osteoclast activation. Metastases also downregulate differentiation and the bone-rebuilding function of osteoblasts. Moreover, cancer cells trigger osteoblast inflammatory stress responses. Pro-inflammatory mediators such as interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1), cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS), expressed by osteoblasts (MC3T3-E1) stimulated with human breast cancer cell (MDA-MB-231) conditioned medium, are pivotal to osteoclast activation and metastasis. Given that these genes are regulated by nuclear factor-kappa B (NF-kappa B), a redox-sensitive transcription factor, we hypothesized that selenium (Se) could abrogate the inflammatory response to metastatic breast cancer cells by modulating NF-kappa B. Caffeic acid phenethyl ester and parthenolide inhibited NF-kappa B activation, as seen by gel shift assays and immunoblotting for p65 in nuclear fractions, as well as decreased production of IL-6 and MCP-1. Supplementation of MC3T3-E1 with methylseleninic acid (MSA) (0.5 mu M to 4 mu M) reduced the activation of NF-kappa B leading to a decrease in IL-6, MCP-1, COX-2 and iNOS in response to MDA-MB-231 conditioned medium. Addition of MSA to osteoblasts for as little as 15 min suppressed activation of NF-kappa B suggesting that short-lived active metabolites might be involved. However, brief exposure to MSA also brought about an increase in selenoprotein glutathione peroxidase 1. In summary, our data indicate that the osteoblast response to metastatic breast cancer cells is regulated by NF-kappa B activation, which can be effectively suppressed by MSA either through short-lived active metabolites and/or selenoproteins. Thus, Se supplementation may prevent the osteoblast inflammatory response or dampen the vicious cycle established when breast cancer cells, osteoblasts and osteoclasts interact.