2-Methoxyestradiol-mediated anti-tumor effect increases osteoprotegrin expression in osteosarcoma cells

Michaela B. Benedikt, Eric W. Mahlum, Kristen L. Shogren, Malayannan Subramaniam, Thomas C. Spelsberg, Michael J. Yaszemski, Avudaiappan Maran

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Osteosarcoma is a bone tumor that frequently develops during adolescence. 2-Methoxyestradiol (2-ME), a naturally occurring metabolite of 17β-estradiol, induces cell cycle arrest and cell death in human osteosarcoma cells. To investigate whether the osteoprotegrin (OPG) protein plays a role in 2-ME actions, we studied the effect of 2-ME treatment on OPG gene expression in human osteosarcoma cells. 2-ME treatment induced OPG gene promoter activity and mRNA levels. Also, Western blot analysis showed that 2-ME treatment increased OPG protein levels in MG63, KHOS, 143B and LM7 osteosarcoma cells by 3-, 1.9-, 2.8-, and 2.5-fold, respectively, but did not affect OPG expression in normal bone cells. In addition, increases in OPG protein levels were observed in osteosarcoma cell culture media after 3 days of 2-ME treatment. The effect of 2-ME on osteosarcoma cells was ligand-specific as parent estrogen, 17β-estradiol and a tumorigenic estrogen metabolite, 16α-hydroxyestradiol, which do not affect osteosarcoma cell cycle and cell death, had no effect on OPG protein expression. Furthermore, cotreating osteosarcoma cells with OPG protein did not further enhance 2-ME-mediated anti-tumor effects. OPG-released in 2-ME-treated cultures led to an increase in osteoblastic activity and a decrease in osteoclast number, respectively. These findings suggest that OPG is not directly involved in 2-ME-mediated anti-proliferative effects in osteosarcoma cells, but rather participates in anti-resorptive functions of 2-ME in bone tumor environment.

Original languageEnglish (US)
Pages (from-to)950-956
Number of pages7
JournalJournal of cellular biochemistry
Volume109
Issue number5
DOIs
StatePublished - Apr 1 2010

Keywords

  • 2-Methoxyestradiol
  • Bone cancer
  • OPG. OPGL
  • Osteosarcoma

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Benedikt, M. B., Mahlum, E. W., Shogren, K. L., Subramaniam, M., Spelsberg, T. C., Yaszemski, M. J., & Maran, A. (2010). 2-Methoxyestradiol-mediated anti-tumor effect increases osteoprotegrin expression in osteosarcoma cells. Journal of cellular biochemistry, 109(5), 950-956. https://doi.org/10.1002/jcb.22473