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- Davoodpour, Padideh,1966-Uppsala universitet,Ludwiginstitutet för cancerforskning (author)
2-ME-Induced Apoptotic Signalling in Prostate Cancer PC3 Cells
- BookEnglish2005
Publisher, publication year, extent ...
- Uppsala :Acta Universitatis Upsaliensis,2005
- 49 s.
- electronicrdacarrier
Numbers
- LIBRIS-ID:oai:DiVA.org:uu-6136
- ISBN:9155464017
- https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6136URI
Supplementary language notes
- Language:English
- Summary in:English
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- SwePubSwePub
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Series
- Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine,1651-6206 ;87
Notes
- 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.
Subject headings and genre
- NATURVETENSKAP Biologi Biokemi och molekylärbiologi hsv//swe
- NATURAL SCIENCES Biological Sciences Biochemistry and Molecular Biology hsv//eng
- Cell and molecular biology
- Prostate cancer
- 2-methoxyestradiol
- apoptosis
- shb
- Smad7
- Cell- och molekylärbiologi
- Cell and molecular biology
- Cell- och molekylärbiologi
Added entries (persons, corporate bodies, meetings, titles ...)
- Landström, Marene (thesis advisor)
- Welsh, Michael (thesis advisor)
- Nilsson, Sten,ProfessorInst. för Onkologi Karolinska Institutet, Stockholm (opponent)
- Uppsala universitetLudwiginstitutet för cancerforskning (creator_code:org_t)
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