Hippo/Mst1 stimulates transcription of the proapoptotic mediator NOXA in a FoxO1-dependent manner
Jazyk angličtina Země Spojené státy americké Médium print-electronic
Typ dokumentu časopisecké články, práce podpořená grantem
PubMed
21245099
DOI
10.1158/0008-5472.can-10-2203
PII: 0008-5472.CAN-10-2203
Knihovny.cz E-zdroje
- MeSH
- alfa-tokoferol farmakologie MeSH
- apoptóza fyziologie MeSH
- forkhead box protein O1 MeSH
- forkhead transkripční faktory genetika metabolismus MeSH
- genetická transkripce MeSH
- intracelulární signální peptidy a proteiny MeSH
- Jurkat buňky MeSH
- lidé MeSH
- lymfom T-buněčný genetika metabolismus patologie terapie MeSH
- malá interferující RNA aplikace a dávkování genetika MeSH
- nádorové buněčné linie MeSH
- nádory plic genetika metabolismus patologie terapie MeSH
- nemalobuněčný karcinom plic genetika metabolismus patologie terapie MeSH
- polymerázová řetězová reakce s reverzní transkripcí MeSH
- promotorové oblasti (genetika) MeSH
- protein-serin-threoninkinasy antagonisté a inhibitory genetika metabolismus MeSH
- protoonkogenní proteiny c-bcl-2 biosyntéza genetika metabolismus MeSH
- signální transdukce MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Názvy látek
- alfa-tokoferol MeSH
- forkhead box protein O1 MeSH
- forkhead transkripční faktory MeSH
- FOXO1 protein, human MeSH Prohlížeč
- intracelulární signální peptidy a proteiny MeSH
- malá interferující RNA MeSH
- PMAIP1 protein, human MeSH Prohlížeč
- protein-serin-threoninkinasy MeSH
- protoonkogenní proteiny c-bcl-2 MeSH
- STK4 protein, human MeSH Prohlížeč
The proapoptotic protein Noxa, a member of the BH3-only Bcl-2 protein family, can effectively induce apoptosis in cancer cells, although the relevant regulatory pathways have been obscure. Previous studies of the cytotoxic effects of α-tocopheryl succinate (α-TOS) on cancer cells identified a mechanism whereby α-TOS caused apoptosis requiring the Noxa-Bak axis. In the present study, ab initio analysis revealed a conserved FoxO-binding site (DBE; DAF-16 binding element) in the NOXA promoter, and specific affinity of FoxO proteins to this DBE was confirmed by fluorescence anisotropy. FoxO1 and FoxO3a proteins accumulated in the nucleus of α-TOS-treated cells, and the drug-induced specific FoxO1 association with the NOXA promoter and its activation were validated by chromatin immunoprecipitation. Using siRNA knockdown, a specific role for the FoxO1 protein in activating NOXA transcription in cancer cells was identified. Furthermore, the proapoptotic kinase Hippo/Mst1 was found to be strongly activated by α-TOS, and inhibiting Hippo/Mst1 by specific siRNA prevented phosphorylation of FoxO1 and its nuclear translocation, thereby reducing levels of NOXA transcription and apoptosis in cancer cells exposed to α-TOS. Thus, we have demonstrated that anticancer drugs, exemplified by α-TOS, induce apoptosis by a mechanism involving the Hippo/Mst1-FoxO1-Noxa pathway. We propose that activation of this pathway provides a new paradigm for developing targeted cancer treatments.
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