2-Methoxyestradiol modulates beta-catenin in prostate cancer cells: a possible mediator of 2-methoxyestradiol-induced inhibition of cell growth.
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.
Van Veldhuizen
Peter J
PJ
Cancer Research Unit, Research Division, V.A. Medical Center, Kansas City, MO 64128, USA. pvanveldhuizen@kumc.edu
Ray
Gibanananda
G
Banerjee
Snigdha
S
Dhar
Gopal
G
Kambhampati
Suman
S
Dhar
Animesh
A
Banerjee
Sushanta K
SK
D000077584:2-Methoxyestradiol; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D056741:Cyclin D; D016213:Cyclins / Q000378:metabolism; D004958:Estradiol / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D009376:Neoplasms, Hormone-Dependent; D010766:Phosphorylation / Q000187:drug effects; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D021381:Protein Transport; D015398:Signal Transduction / Q000187:drug effects; D013347:Subcellular Fractions; D051820:TCF Transcription Factors / Q000378:metabolism; D050257:Tubulin Modulators / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism*
D056741:Cyclin D; D016213:Cyclins; D051820:TCF Transcription Factors; D050257:Tubulin Modulators; D051176:beta Catenin; D004958:Estradiol; D000077584:2-Methoxyestradiol; D019950:Mitogen-Activated Protein Kinase 1; D048369:MAP Kinase Kinase 1; C482125:MAP2K1 protein, human