Multiple defects in negative regulation of the PKB/Akt pathway sensitise human cancer cells to the antiproliferative effect of non-steroidal anti-inflammatory drugs
Jazyk angličtina Země Anglie, Velká Británie Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
19433066
DOI
10.1016/j.bcp.2009.05.001
PII: S0006-2952(09)00375-X
Knihovny.cz E-zdroje
- MeSH
- antiflogistika nesteroidní farmakologie MeSH
- antitumorózní látky farmakologie MeSH
- buněčný cyklus účinky léků fyziologie MeSH
- enzymová indukce MeSH
- epitelové buňky účinky léků patologie MeSH
- exprese genu účinky léků MeSH
- extracelulárním signálem regulované MAP kinasy metabolismus MeSH
- fosfatidylinositol-3-kinasy MeSH
- indomethacin farmakologie MeSH
- inhibitor p21 cyklin-dependentní kinasy biosyntéza MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- nádorový supresorový protein p53 genetika metabolismus MeSH
- nádory prostaty patologie MeSH
- proteiny buněčného cyklu metabolismus MeSH
- protoonkogenní proteiny c-akt metabolismus MeSH
- RNA interference MeSH
- růstový diferenciační faktor 15 biosyntéza MeSH
- signální transdukce účinky léků fyziologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- antiflogistika nesteroidní MeSH
- antitumorózní látky MeSH
- extracelulárním signálem regulované MAP kinasy MeSH
- fosfatidylinositol-3-kinasy MeSH
- indomethacin MeSH
- inhibitor p21 cyklin-dependentní kinasy MeSH
- nádorový supresorový protein p53 MeSH
- proteiny buněčného cyklu MeSH
- protoonkogenní proteiny c-akt MeSH
- růstový diferenciační faktor 15 MeSH
Antitumorigenic effects of non-steroidal anti-inflammatory drugs (NSAIDs) are well established in several types of cancer disease. However, the mechanisms driving these processes are not understood in all details. In our study, we observed significant differences in sensitivity of cancer epithelial cell lines to COX-independent antiproliferative effects of NSAIDs. The prostate cancer cell line LNCaP, lacking both critical enzymes in the negative control of PKB/Akt activation, PTEN and SHIP2, was the most sensitive to these effects, as assessed by analysing the cell cycle profile and expression of cell cycle regulating proteins. We found that p53 protein and its signalling pathway is not involved in early antiproliferative action of the selected NSAID-indomethacin. RNAi provided evidence for the involvement of p21(Cip1/Waf1), but not GDF-15, in antiproliferative effects of indomethacin in LNCaP cells. Interestingly, we also found that indomethacin activated PKB/Akt and induced nuclear localisation of p21(Cip1/Waf1) and Akt2 isoform. Our results are in agreement with other studies and suggest that maintaining of the p21(Cip1/Waf1) level and its intracellular localisation might be influenced by Akt2. Knock-down of SHIP2 by RNAi in PTEN negative prostate and colon cancer cell lines resulted in higher sensitivity to antiproliferative effects of indomethacin. Our data suggest novel mechanisms of NSAIDs antiproliferative action in cancer epithelial cells, which depends on the status of negative regulation of the PKB/Akt pathway and the isoform-specific action of Akt2. Thus, unexpectedly, multiple defects in negative regulation of the PKB/Akt pathway may contribute to increased sensitivity to chemopreventive effects of these widely used drugs.
Citace poskytuje Crossref.org
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