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2-Methoxyestradiol-induced apoptosis in prostate cancer cells requires Smad7
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
2005 (English)In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 280, no 15, 14773-14779 p.Article in journal (Refereed) Published
Abstract [en]

Prostate cancer is the second most common cause of death related to cancer in Western society. 2-Methoxyestradiol (2-ME), an endogenous metabolite of estradiol-17beta, inhibits tumor angiogenesis while also exerting potent cytotoxic effects on various cancer cells. 2-ME has been shown to activate the p38 MAPK and JNK pathways and to induce apoptosis in cells, although the underlying molecular mechanisms for this are unknown. Here we report that the expression of Smad7, an adaptor molecule required to activate p38 MAPK in the transforming growth factor beta signaling pathway, is also required for 2-ME-induced p38 activation and apoptosis in human prostate cancer cells (PC-3U). PC-3U/AS-S7 cells stably transfected with an antisense Smad7 construct, or PC-3U cells transiently transfected with short interfering RNA for Smad7, were protected against 2-ME-induced apoptosis. 2-ME-induced apoptosis was found to involve p38 MAPK and JNK, because simultaneous treatments with 2-ME and a specific p38 inhibitor (SB203580) or an inhibitor of JNK (L-JNK1) prevented 2-ME-induced apoptosis. Most interestingly, Smad7 was shown by both antisense and short interfering RNA techniques to affect levels of beta-catenin, which has been implicated previously in the regulation of apoptosis. Moreover, Smad7 was found to be important for the basal expression of Bim, a pro-apoptotic Bcl-2 family member, and for 2-ME-induced expression of Bim. These results suggest that expression of Smad7 is crucial for 2-ME-induced apoptosis in human prostate cancer cells.

Place, publisher, year, edition, pages
2005. Vol. 280, no 15, 14773-14779 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-93756DOI: 10.1074/jbc.M414470200PubMedID: 15708859OAI: oai:DiVA.org:uu-93756DiVA: diva2:167334
Available from: 2005-11-17 Created: 2005-11-17 Last updated: 2013-10-30Bibliographically approved
In thesis
1. 2-ME-Induced Apoptotic Signalling in Prostate Cancer PC3 Cells
Open this publication in new window or tab >>2-ME-Induced Apoptotic Signalling in Prostate Cancer PC3 Cells
2005 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Prostate cancer is common in the Western society and current treatments are often associated with side effects, therefore improved therapeutic strategies are desired. 2-methoxyestradiol (2-ME), an endogenous metabolite of estradiol-17β inhibits tumor growth in vivo as it prevents angiogenesis. 2-ME has also direct cytotoxic effects on tumor cells. In this study, we have investigated the potential use of PET to record effects 2-ME on prostate cancer cell (PC3) aggregates. The anti-proliferative and pro-apoptotic effects of 2-ME on PC3 cell aggregates in vitro were correlated with the uptake of deoxy-D-glucose, FMAU and choline labeled with 18F, 11C or 3H. 2-ME clearly reduced growth of PC3 aggregates and induced apoptosis in a dose-dependent manner. However, the PET tracers failed to record the cytotoxicity of 2-ME on PC3 aggregates.

Further, the signaling events responsible for 2-ME induced prostate cancer cell death were investigated. We found that Smad7, previously implicated in TGF-β-induced responses, is required for 2-ME-induced p38 MAPK activation and subsequent apoptosis in PC-3U cells, as shown by the use of antisense or siRNA techniques and a specific inhibitor of p38 MAPK (SB203580). Interestingly, Smad7 also regulated the expression of the pro-apoptotic Bim protein.

Shb is a Src Homology 2 domain adapter protein with pro-apoptotic effects. PC3 clones overexpressing Shb exhibited increased rates of apoptosis, both in the presence or absence of 2-ME, as they failed to activate survival mechanisms through ERK and Akt in response to 2-ME. Notably, Shb cells displayed increased activity of the pro-apoptotic kinase c-Abl. Pre-treatment with SB203580 or c-Abl (STI-571) inhibitors completely blocked the apoptotic response to 2-ME.

In conclusion, Smad7 and Shb appear to be crucial for 2-ME-induced PC3 cell apoptosis via their activation of p38 MAPK and c-Abl. Future therapies exploring these pathways can be envisaged as treatment of prostate cancer.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2005. 49 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 87
Cell and molecular biology, Prostate cancer, 2-methoxyestradiol, apoptosis, shb, Smad7, Cell- och molekylärbiologi
National Category
Biochemistry and Molecular Biology
urn:nbn:se:uu:diva-6136 (URN)91-554-6401-7 (ISBN)
Public defence
2005-12-09, Room B22, BMC, Husargatan 3, Uppsala, 09:15
Available from: 2005-11-17 Created: 2005-11-17Bibliographically approved

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