Nuclear Factor of Activated T Cells-dependent Down-regulation of the Transcription Factor Glioma-associated Protein 1 (GLI1) Underlies the Growth Inhibitory Properties of Arachidonic Acid
| العنوان: | Nuclear Factor of Activated T Cells-dependent Down-regulation of the Transcription Factor Glioma-associated Protein 1 (GLI1) Underlies the Growth Inhibitory Properties of Arachidonic Acid |
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| المؤلفون: | Ezequiel J. Tolosa, R.A. Silva, Martin E. Fernandez-Zapico, Maite G. Fernandez-Barrena, Eriko Iguchi, Lucia Di Marcotulio, Aldo R. Eynard, Luciana L. Almada, Bruno Botta, Marianela Vara Messler, Andrea Comba, Volker Ellenrieder, David L. Marks, M.E. Pasqualini, Elisa Enriquez-Hesles, Anne L. Vrabel |
| المصدر: | CONICET Digital (CONICET) Consejo Nacional de Investigaciones Científicas y Técnicas instacron:CONICET |
| بيانات النشر: | Elsevier BV, 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | 0301 basic medicine, Programmed cell death, GLI1, arachidonic acid (AA) (ARA), cancer, cell death, polyunsaturated fatty acid (PUFA), transcription factor, Chromosomal Puffs, Down-Regulation, Biology, Zinc Finger Protein GLI1, Biochemistry, Mice, 03 medical and health sciences, Transcription (biology), ARACHIDONIC ACID, Cell Line, Tumor, Neoplasms, Animals, Humans, Promoter Regions, Genetic, Molecular Biology, Transcription factor, Cell Proliferation, chemistry.chemical_classification, Reactive oxygen species, Arachidonic Acid, NFATC Transcription Factors, integumentary system, Cell growth, Molecular Bases of Disease, purl.org/becyt/ford/3.1 [https], Cell Biology, CANCER, Molecular biology, APOPTOSIS, 3. Good health, Gene Expression Regulation, Neoplastic, 030104 developmental biology, chemistry, purl.org/becyt/ford/3 [https], Signal transduction, Chromatin immunoprecipitation, Signal Transduction, Transcription Factors |
| الوصف: | Numerous reports have demonstrated a tumor inhibitory effect of polyunsaturated fatty acids (PUFAs). However, the molecular mechanisms modulating this phenomenon are in part poorly understood. Here, we provide evidence of a novel antitumoral mechanism of the PUFA arachidonic acid (AA). In vivo and in vitro experiments showed that AA treatment decreased tumor growth and metastasis and increased apoptosis. Molecular analysis of this effect showed significantly reduced expression of a subset of antiapoptotic proteins, including BCL2, BFL1/A1, and 4-1BB, in AA-treated cells.Wedemonstrated that down-regulation of the transcription factor gliomaassociated protein 1 (GLI1) in AA-treated cells is the underlying mechanism controlling BCL2, BFL1/A1, and 4-1BB expression. Using luciferase reporters, chromatin immunoprecipitation, and expression studies, we found that GLI1 binds to the promoter of these antiapoptotic molecules and regulates their expression and promoter activity. We provide evidence that AA-induced apoptosis and down-regulation of antiapoptotic genes can be inhibited by overexpressing GLI1 in AA-sensitive cells. Conversely, inhibition of GLI1 mimics AA treatments, leading to decreased tumor growth, cell viability, and expression of antiapoptotic molecules. Further characterization showed thatAArepresses GLI1 expression by stimulating nuclear translocation of NFATc1, which then binds the GLI1 promoter and represses its transcription. AA was shown to increase reactive oxygen species. Treatment with antioxidants impaired the AAinduced apoptosis and down-regulation of GLI1 and NFATc1 activation, indicating that NFATc1 activation and GLI1 repression require the generation of reactive oxygen species. Collectively, these results define a novel mechanism underlying AA antitumoral functions that may serve as a foundation for future PUFA-based therapeutic approaches. Fil: Comba, Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina Fil: Almada, Luciana Victoria. Mayo Clinic - Schuze Center Of Novel Therapeutic; Estados Unidos Fil: Tolosa, Ezequiel J.. Mayo Clinic - Schuze Center Of Novel Therapeutic; Estados Unidos Fil: Iguchi, Eriko. Mayo Clinic - Schuze Center Of Novel Therapeutic; Estados Unidos Fil: Marks, David L.. Mayo Clinic - Schuze Center Of Novel Therapeutic; Estados Unidos Fil: Vara Messler, Marianela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina Fil: Silva, Renata Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina Fil: Fernandez-Barrena, Maite G.. Mayo Clinic - Schuze Center Of Novel Therapeutic; Estados Unidos Fil: Enriquez-Hesles, Elisa. Mayo Clinic - Schuze Center Of Novel Therapeutic; Estados Unidos Fil: Vrabel, Anne L.. Mayo Clinic - Schuze Center Of Novel Therapeutic; Estados Unidos Fil: Botta, Bruno. Sapienza University; Italia Fil: Di Marcotulio, Lucia. Sapienza University; Italia Fil: Ellenrieder, Volker. University Medical Center Göttingen; Alemania Fil: Eynard, Aldo Renato. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina Fil: Pasqualini, María Eugenia. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigaciones en Ciencias de la Salud. Universidad Nacional de Córdoba. Instituto de Investigaciones en Ciencias de la Salud; Argentina Fil: Fernandez Zapico, Martin Ernesto. Mayo Clinic - Schuze Center Of Novel Therapeutic; Estados Unidos |
| وصف الملف: | application/pdf |
| تدمد: | 0021-9258 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a1d74f80e0147965121f6e9b40527a2bTest https://doi.org/10.1074/jbc.m115.691972Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....a1d74f80e0147965121f6e9b40527a2b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 00219258 |
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