2-Methoxyestradiol modulates β-catenin in prostate cancer cells: A possible mediator of 2-methoxyestradiol-induced inhibition of cell growth

Abstract

2-Methoxyestradiol (2-ME2) is a novel anticancer agent because of its ability to potentiate apoptotic cell death and inhibit cancer cell growth and angiogenesis. The modes of action of this agent, however, have not yet been fully elucidated. In our study, we have investigated whether 2-ME2 is able to modulate β-catenin signaling in prostate cancer cells, which is one of the major players in cell-cell adhesion, proliferation, apoptosis and carcinogenesis. We found that β-catenin levels were significantly upregulated by 2-ME2 in a dose-dependent manner in androgen dependent and independent prostate cancer total cellular extracts. We further show that β-catenin levels were significantly increased in the membrane fraction, while nuclear fractions of β-catenin were downregulated in the 2-ME 2-treated cells. Accumulation of dephospho-β-catenin (nondegraded form) parallel with Bcl-2 and Cyclin D1 downregulation was also achieved after 2-ME2 treatment. Moreover, we demonstrate that the β-catenin production by 2-ME2 is mediated through the MEK/ERK-2 signaling pathway. Collectively, these results suggest that the cytostatic effect of 2-ME2 may be mediated through the prevention of the translocation of β-catenin to the nucleus parallel with an increase in cell-cell adhesion by increasing membrane β-catenin production, eventually preventing cell migration. Moreover, dephospho-β-catenin accumulation by 2ME2 in the cytoplasm may contribute to the induction of apoptosis of these cells. Finally, studies testing the efficacy of 2-ME2 in human prostate cancer are warranted to determine whether the inhibition of the expected loss of membranous β-catenin and the upregulation of nuclear β-catenin can prevent prostate cancer development and progression. © 2007 Wiley-Liss, Inc.