Hippo/Mst1 stimulates transcription of the proapoptotic mediator NOXA in a FoxO1-dependent manner
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
21245099
DOI
10.1158/0008-5472.can-10-2203
PII: 0008-5472.CAN-10-2203
Knihovny.cz E-resources
- MeSH
- alpha-Tocopherol pharmacology MeSH
- Apoptosis physiology MeSH
- Forkhead Box Protein O1 MeSH
- Forkhead Transcription Factors genetics metabolism MeSH
- Transcription, Genetic MeSH
- Intracellular Signaling Peptides and Proteins MeSH
- Jurkat Cells MeSH
- Humans MeSH
- Lymphoma, T-Cell genetics metabolism pathology therapy MeSH
- RNA, Small Interfering administration & dosage genetics MeSH
- Cell Line, Tumor MeSH
- Lung Neoplasms genetics metabolism pathology therapy MeSH
- Carcinoma, Non-Small-Cell Lung genetics metabolism pathology therapy MeSH
- Reverse Transcriptase Polymerase Chain Reaction MeSH
- Promoter Regions, Genetic MeSH
- Protein Serine-Threonine Kinases antagonists & inhibitors genetics metabolism MeSH
- Proto-Oncogene Proteins c-bcl-2 biosynthesis genetics metabolism MeSH
- Signal Transduction MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- alpha-Tocopherol MeSH
- Forkhead Box Protein O1 MeSH
- Forkhead Transcription Factors MeSH
- FOXO1 protein, human MeSH Browser
- Intracellular Signaling Peptides and Proteins MeSH
- RNA, Small Interfering MeSH
- PMAIP1 protein, human MeSH Browser
- Protein Serine-Threonine Kinases MeSH
- Proto-Oncogene Proteins c-bcl-2 MeSH
- STK4 protein, human MeSH Browser
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.
References provided by Crossref.org
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