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Increased apoptosis and C-Abl activity in PC3 prostate cancer overexpressing the Shb adapter protein
Uppsala University, Units outside the University, Ludwig Institute for Cancer Research.
Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-93757OAI: oai:DiVA.org:uu-93757DiVA: diva2:167335
Available from: 2005-11-17 Created: 2005-11-17 Last updated: 2010-01-13Bibliographically 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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