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Open Access Research article

Regulation of interferon pathway in 2-methoxyestradiol-treated osteosarcoma cells

Fritz Wimbauer12, Caihong Yang13, Kristen L Shogren1, Minzhi Zhang1, Ribu Goyal1, Scott M Riester1, Michael J Yaszemski12 and Avudaiappan Maran12*

Author affiliations

1 Department of Orthopedics, College of Medicine, Mayo Clinic, 3-69 Medical Sciences, Rochester, MN 55906, USA

2 Paracelsus Medical University, Salzburg 5020, Austria

3 Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China

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Citation and License

BMC Cancer 2012, 12:93  doi:10.1186/1471-2407-12-93

Published: 19 March 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