Carcinogenesis Advance Access originally published online on September 16, 2009
Carcinogenesis 2009 30(11):1941-1948; doi:10.1093/carcin/bgp227
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Selenium modifies the osteoblast inflammatory stress response to bone metastatic breast cancer
Department of Biochemistry and Molecular Biology, 431 South Frear Building, Penn State University, University Park, PA 16802, USA
1 Department of Veterinary and Biomedical Sciences, 115 Henning Building, Penn State University, University Park, PA 16802, USA
* To whom correspondence should be addressed. Tel: +1 814 863 0152; Fax: +1 814 863 7024; Email: a36{at}psu.edu
Correspondence may also be addressed to K.Sandeep Prabhu. Tel: +1 814 863 8976; Fax: +1 814 863 6140; Email: ksp4{at}psu.edu
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-
B (NF-B), a redox-sensitive transcription factor, we hypothesized that selenium (Se) could abrogate the inflammatory response to metastatic breast cancer cells by modulating NF-B. Caffeic acid phenethyl ester and parthenolide inhibited NF-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 µM to 4 µM) reduced the activation of NF-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-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-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.
Abbreviations: BCCM, breast cancer cell-conditioned medium; CAPE, caffeic acid phenethyl ester; COX-2, cyclooxygenase-2; DMSO, dimethyl sulfoxide; EMSA, electrophoretic mobility shift assay; FBS, fetal bovine serum; GPx, glutathione peroxidase; IL, interleukin; iNOS, inducible nitric oxide synthase; MCP-1, monocyte chemoattractant protein-1; MSA, methylseleninic acid; NF-B, nuclear factor-B; Se, selenium; TGF, transforming growth factor; TR, thioredoxin reductase; VM, vehicle control medium
Received February 13, 2009; revised September 10, 2009; accepted September 12, 2009.