2-Methoxyestradiol Inhibits the Anaphase-Promoting Complex and Protein Translation in Human Breast Cancer Cells

Bhati, Rajendra; Gökmen–Polar, Yesim; Sledge, George W.; Fan, Cheng; Nakshatri, Harikrishna; Ketelsen, David; Borchers, Christoph H.; Dial, Michael J.; Patterson, Cam; Klauber-DeMore, Nancy

doi:10.1158/0008-5472.can-06-3406

Cited by 25 publications

(38 citation statements)

References 28 publications

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“…4,25,36 Although the mode of action of this estrogen metabolite has not yet been fully elucidated, multiple studies have demonstrated that 2-ME 2 modulates several crucial genes linked with the cell-cycle regulation. 4,5,16,25,[37][38][39][40][41][42][43][44][45] In our study, for the first time, we postulate the possible involvement of b-catenin and its receptor, TCF-3/4 transcription factor, in the significant effect of 2-ME 2 on prostate cancer cells.…”

Section: Discussionmentioning

confidence: 87%

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

Veldhuizen

Ray

Banerjee

et al. 2007

Intl Journal of Cancer

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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 b-catenin signaling in prostate cancer cells, which is one of the major players in cell-cell adhesion, proliferation, apoptosis and carcinogenesis. We found that b-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 b-catenin levels were significantly increased in the membrane fraction, while nuclear fractions of b-catenin were downregulated in the 2-ME 2 -treated cells. Accumulation of dephospho-b-catenin (nondegraded form) parallel with Bcl-2 and Cyclin D1 downregulation was also achieved after 2-ME 2 treatment. Moreover, we demonstrate that the b-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 b-catenin to the nucleus parallel with an increase in cell-cell adhesion by increasing membrane b-catenin production, eventually preventing cell migration. Moreover, dephospho-b-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 b-catenin and the upregulation of nuclear b-catenin can prevent prostate cancer development and progression. ' 2007 Wiley-Liss, Inc.

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Section: Discussionmentioning

confidence: 87%

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

Veldhuizen

Ray

Banerjee

et al. 2007

Intl Journal of Cancer

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“…2ME2 inhibits the spindle assembly checkpoint in mitosis by delaying the onset of anaphase (27). This effect can occur due to insufficient microtubule assembly to form a bipolar spindle or reduced microtubule dynamics that compromise the tension required on sister kinetochores to ensure correct separation and segregation of chromosomes.…”

Section: Discussionmentioning

confidence: 99%

Class I β-tubulin mutations in 2-methoxyestradiol-resistant acute lymphoblastic leukemia cells: implications for drug-target interactions

Liaw

Salam

McKay

et al. 2008

Molecular Cancer Therapeutics

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2-Methoxyestradiol (2ME2) is a naturally occurring derivative of estradiol that has been shown to be an active small molecule that has antitumor and antiangiogenic properties. 2ME2 binds to B-tubulin near the colchicinebinding site, inhibits microtubule polymerization, and induces mitotic arrest. To improve understanding of the mechanisms of action and resistance to 2ME2, we selected leukemia cells, CCRF-CEM, that display increasing resistance to 2ME2, and three of the highly resistant sublines were chosen for detailed analysis. The 2ME2 cells selected in 7.2 to 28.8 Mmol/L were found to be 47-to 107-fold resistant to 2ME2 and exhibited low levels of cross-resistance to vinblastine. Two of the lowest 2ME2-resistant sublines were significantly hypersensitive to colchicine and epothilone B, but the hypersensitive effects were lost in the highest 2ME2-resistant subline. Moreover, 2ME2-resistant cells require 10-fold higher concentrations of 2ME2 to induce G 2 -M cell cycle arrest and have higher amounts of tubulin polymer compared with parental cells. Gene and protein sequencing revealed four class I B-tubulin mutations, S25N, D197N, A248T, and K350N, in the 2ME2-resistant cells. The S25N mutation is within the paclitaxel-binding site, whereas A248T and K350N are within the colchicine-binding site on B-tubulin, yet the resistant cells were not cross-resistant to paclitaxel or colchicine. This strongly suggests that the mutations have induced conformational changes to the binding site that resulted in 2ME2 resistance. The 2ME2-resistant leukemia cells provide novel insights into microtubule stability and drug-target interactions. [Mol Cancer Ther 2008;7(10):3150 -9]

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“…The NCD formulation of 2ME was shown to have improved bioavailability resulting in plasma concentration levels within the range needed for anti-tumor activity [3]. 2ME plays as role in the abrogation of microtubule dynamics and the inhibition of protein translation and activity of the anaphase-promoting complex (APC/C) [6]. 2ME inhibits angiogenesis by interacting with endothelial tubulin dynamics which in turn negatively affects the expression and activity of hypoxiainducible factor 1-alpha (HIF-1a) and vascular endothelial growth factor (VEGF) [7,8].…”

Section: Introductionmentioning

confidence: 99%

In vitro effects of 2-methoxyestradiol on morphology, cell cycle progression, cell death and gene expression changes in the tumorigenic MCF-7 breast epithelial cell line

Stander

Marais

Vorster

et al. 2010

The Journal of Steroid Biochemistry and Molecular Biology

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2-Methoxyestradiol Inhibits the Anaphase-Promoting Complex and Protein Translation in Human Breast Cancer Cells

Cited by 25 publications

References 28 publications

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

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

Class I β-tubulin mutations in 2-methoxyestradiol-resistant acute lymphoblastic leukemia cells: implications for drug-target interactions

In vitro effects of 2-methoxyestradiol on morphology, cell cycle progression, cell death and gene expression changes in the tumorigenic MCF-7 breast epithelial cell line

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