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Hippo/Mst1 stimulates transcription of the proapoptotic mediator NOXA in a FoxO1-dependent manner.

Abstract
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.
AuthorsKarel Valis, Lubomir Prochazka, Evzen Boura, Jaromira Chladova, Tomas Obsil, Jakub Rohlena, Jaroslav Truksa, Lan-Feng Dong, Stephen J Ralph, Jiri Neuzil
JournalCancer research (Cancer Res) Vol. 71 Issue 3 Pg. 946-54 (Feb 01 2011) ISSN: 1538-7445 [Electronic] United States
PMID21245099 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • FOXO1 protein, human
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors
  • Intracellular Signaling Peptides and Proteins
  • PMAIP1 protein, human
  • Proto-Oncogene Proteins c-bcl-2
  • RNA, Small Interfering
  • STK4 protein, human
  • Protein Serine-Threonine Kinases
  • alpha-Tocopherol
Topics
  • Apoptosis (physiology)
  • Carcinoma, Non-Small-Cell Lung (genetics, metabolism, pathology, therapy)
  • Cell Line, Tumor
  • Forkhead Box Protein O1
  • Forkhead Transcription Factors (genetics, metabolism)
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Jurkat Cells
  • Lung Neoplasms (genetics, metabolism, pathology, therapy)
  • Lymphoma, T-Cell (genetics, metabolism, pathology, therapy)
  • Promoter Regions, Genetic
  • Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics, metabolism)
  • Proto-Oncogene Proteins c-bcl-2 (biosynthesis, genetics, metabolism)
  • RNA, Small Interfering (administration & dosage, genetics)
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction
  • Transcription, Genetic
  • alpha-Tocopherol (pharmacology)

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