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

Fritz Wimbauer, Caihong Yang, Kristen L. Shogren, Minzhi Zhang, Ribu Goyal, Scott M. Riester, Michael J Yaszemski, Avudaiappan Maran

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16 Scopus citations

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.

Original languageEnglish (US)
Article number93
JournalBMC Cancer
Volume12
DOIs
StatePublished - Mar 19 2012

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Keywords

  • 2-methoxyestradiol
  • GAS
  • Interferon
  • ISRE
  • Osteosarcoma

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics

Cite this

Wimbauer, F., Yang, C., Shogren, K. L., Zhang, M., Goyal, R., Riester, S. M., Yaszemski, M. J., & Maran, A. (2012). Regulation of interferon pathway in 2-methoxyestradiol-treated osteosarcoma cells. BMC Cancer, 12, [93]. https://doi.org/10.1186/1471-2407-12-93