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2‐Methoxyestradiol modulates β‐catenin in prostate cancer cells: A possible mediator of 2‐methoxyestradiol‐induced inhibition of cell growth
Author(s) -
Van Veldhuizen Peter J.,
Ray Gibanananda,
Banerjee Snigdha,
Dhar Gopal,
Kambhampati Suman,
Dhar Animesh,
Banerjee Sushanta K.
Publication year - 2007
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.23117
Subject(s) - cell growth , cancer research , catenin , apoptosis , prostate cancer , cancer cell , programmed cell death , microbiology and biotechnology , downregulation and upregulation , cell adhesion , biology , cell , cell cycle , chemistry , signal transduction , cancer , wnt signaling pathway , medicine , biochemistry , gene
2‐Methoxyestradiol (2‐ME 2 ) 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‐ME 2 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‐ME 2 treatment. Moreover, we demonstrate that the β‐catenin production by 2‐ME 2 is mediated through the MEK/ERK‐2 signaling pathway. Collectively, these results suggest that the cytostatic effect of 2‐ME 2 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 2ME 2 in the cytoplasm may contribute to the induction of apoptosis of these cells. Finally, studies testing the efficacy of 2‐ME 2 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.