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BMC Cancer. 2012; 12: 93.
Published online Mar 19, 2012. doi:  10.1186/1471-2407-12-93
PMCID: PMC3414746
Regulation of interferon pathway in 2-methoxyestradiol-treated osteosarcoma cells
Fritz Wimbauer,#1,2 Caihong Yang,#1,3 Kristen L Shogren,1 Minzhi Zhang,1 Ribu Goyal,1 Scott M Riester,1 Michael J Yaszemski,1,2 and Avudaiappan Marancorresponding author1,2
1Department of Orthopedics, College of Medicine, Mayo Clinic, 3-69 Medical Sciences, Rochester, MN 55906, USA
2Paracelsus Medical University, Salzburg 5020, Austria
3Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
corresponding authorCorresponding author.
#Contributed equally.
Fritz Wimbauer: f.wimbauer/at/pmu.ac.at; Caihong Yang: yangcaihong/at/tjh.tjmu.edu.cn; Kristen L Shogren: shogren.kristen/at/mayo.edu; Minzhi Zhang: zhang.minzhi/at/mayo.edu; Ribu Goyal: goyal.ribu/at/mayo.edu; Scott M Riester: riester.scott/at/mayo.edu; Michael J Yaszemski: yaszemski.michael/at/mayo.edu; Avudaiappan Maran: maran.avudai/at/mayo.edu
Received August 23, 2011; Accepted March 19, 2012.
Abstract
Background
Osteosarcoma is a bone tumor that often affects children and young adults. Although a combination of surgery and chemotherapy has improved the survival rate in the past decades, local recurrence and metastases still develop in 40% of patients. A definite therapy is yet to be determined for osteosarcoma. Anti- tumor compound and a metabolite of estrogen, 2-methoxyestradiol (2-ME) induces cell death in osteosarcoma cells. In this report, we have investigated whether interferon (IFN) pathway is involved in 2-ME-induced anti-tumor effects in osteosarcoma cells.
Methods
2-ME effects on IFN mRNA levels were determined by Real time PCR analysis. Transient transfections followed by reporter assays were used for investigating 2-ME effects on IFN-pathway. Western blot analyses were used to measure protein and phosphorylation levels of IFN-regulated eukaryotic initiation factor-2 alpha (eIF-2α).
Results
2-ME regulates IFN and IFN-mediated effects in osteosarcoma cells. 2 -ME induces IFN gene activity and expression in osteosarcoma cells. 2-ME treatment induced IFN-stimulated response element (ISRE) sequence-dependent transcription and gamma-activated sequence (GAS)-dependent transcription in several osteosarcoma cells. Whereas, 2-ME did not affect IFN gene and IFN pathways in normal primary human osteoblasts (HOB). 2-ME treatment increased the phosphorylation of eIF-2α in osteosarcoma cells. Furthermore, analysis of osteosarcoma tissues shows that the levels of phosphorylated form of eIF-2α are decreased in tumor compared to normal controls.
Conclusions
2-ME treatment triggers the induction and activity of IFN and IFN pathway genes in 2-ME-sensitive osteosarcoma tumor cells but not in 2-ME-resistant normal osteoblasts. In addition, IFN-signaling is inhibited in osteosarcoma patients. Thus, IFN pathways play a role in osteosarcoma and in 2-ME-mediated anti-proliferative effects, and therefore targeted induction of IFN signaling could lead to effective treatment strategies in the control of osteosarcoma.
Keywords: 2-Methoxyestradiol, osteosarcoma, Interferon, ISRE, GAS
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