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2-Methoxyestradiol modulates beta-catenin in prostate cancer cells: a possible mediator of 2-methoxyestradiol-induced inhibition of cell growth.
- Source :
-
International journal of cancer [Int J Cancer] 2008 Feb 01; Vol. 122 (3), pp. 567-71. - Publication Year :
- 2008
-
Abstract
- 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 beta-catenin signaling in prostate cancer cells, which is one of the major players in cell-cell adhesion, proliferation, apoptosis and carcinogenesis. We found that beta-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 beta-catenin levels were significantly increased in the membrane fraction, while nuclear fractions of beta-catenin were downregulated in the 2-ME(2)-treated cells. Accumulation of dephospho-beta-catenin (nondegraded form) parallel with Bcl-2 and Cyclin D1 downregulation was also achieved after 2-ME(2) treatment. Moreover, we demonstrate that the beta-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 beta-catenin to the nucleus parallel with an increase in cell-cell adhesion by increasing membrane beta-catenin production, eventually preventing cell migration. Moreover, dephospho-beta-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 beta-catenin and the upregulation of nuclear beta-catenin can prevent prostate cancer development and progression.<br /> ((c) 2007 Wiley-Liss, Inc.)
- Subjects :
- 2-Methoxyestradiol
Blotting, Western
Cell Nucleus metabolism
Cyclin D
Cyclins metabolism
Estradiol pharmacology
Humans
MAP Kinase Kinase 1 metabolism
Male
Mitogen-Activated Protein Kinase 1 metabolism
Neoplasms, Hormone-Dependent
Phosphorylation drug effects
Prostatic Neoplasms metabolism
Prostatic Neoplasms pathology
Protein Transport
Signal Transduction drug effects
Subcellular Fractions
TCF Transcription Factors metabolism
Tumor Cells, Cultured drug effects
Apoptosis drug effects
Cell Proliferation drug effects
Estradiol analogs & derivatives
Prostatic Neoplasms drug therapy
Tubulin Modulators pharmacology
beta Catenin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1097-0215
- Volume :
- 122
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- International journal of cancer
- Publication Type :
- Academic Journal
- Accession number :
- 17935127
- Full Text :
- https://doi.org/10.1002/ijc.23117