Osteosarcoma is a bone tumor that occurs most frequently during adolescence. Although a combination of surgery and chemotherapy has led to improved survival rate, a specific therapy is not yet available for this devastating disease and the mortality rate is still quite high. The proposed research will focus on a promising new treatment based on the unique activity of an estrogen metabolite, 2-Methoxyestradiol (2-ME), to prevent the growth of tumor cells (tumorstatic) and to kill residual tumor cells (tumoricidal). The gonadal hormone, 17beta-estradiol is metabolized into functional molecules that elicit unique effects on biological processes in estrogen target tissues. While some metabolites of 17beta-estradiol, namely, 4- and 16alpha-hydroxyestradiols may be cancer promoters; others like 2-ME is hypothesized to prevent cancer. Our work has shown that 2-ME is effective in killing osteosarcoma cells (bone cancer cells) and not normal osteoblasts. The objective of this project is to understand the molecular mechanism associated with the anti-cancer activities of 2-ME in osteosarcoma cells. The preliminary results demonstrate that interferon gene expression is dramatically stimulated in 2-ME treated cells. 2-ME treatment also inhibited the cell cycle progression from G0/G1 phase to S phase. Based on these findings, our working hypothesis is that interferon mediates, at least in part, the anti-tumor activity of 2-ME. This investigation will test the hypothesis that anti-cancer effects of 2-ME in osteosarcoma cells involve interferon pathways by accomplishing the following specific aims in cultured human osteosarcoma cells: 1) To determine whether interferon gene expression is essential for 2-ME effects; 2) To establish the involvement of specific interferon-regulated pathways (e.g., PKR, RNase L and STAT) in 2-ME mediated action; and 3) To determine whether genes associated with cell-cycle regulation play a role in 2-ME mediated induction of interferon and osteosarcoma cell death. Apart from providing new insights into the functional role of estrogen metabolites in tumor cells, these studies could help identify molecular therapeutic targets and open new avenues in the treatment of osteosarcoma.
|Maran, Avudaiappan; Shogren, Kristen L; Benedikt, Michaela et al. (2008) 2-methoxyestradiol-induced cell death in osteosarcoma cells is preceded by cell cycle arrest. J Cell Biochem 104:1937-45|
|Shogren, Kristen L; Turner, Russell T; Yaszemski, Michael J et al. (2007) Double-stranded RNA-dependent protein kinase is involved in 2-methoxyestradiol-mediated cell death of osteosarcoma cells. J Bone Miner Res 22:29-36|
|Maran, A; Gorny, G; Oursler, M J et al. (2006) 2-methoxyestradiol inhibits differentiation and is cytotoxic to osteoclasts. J Cell Biochem 99:425-34|