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J Biol Chem. 2016 Jan 22;291(4):1933-47. doi: 10.1074/jbc.M115.691972. Epub 2015 Nov 24.

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.

Author information

1
From the Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, Instituto de Investigaciones en Ciencias de la Salud, Consejo Nacional de Investigaciones Científicas y Técnicas and Facultad de Ciencias Médicas-Universidad Nacional de Córdoba, Ciudad Universitaria, 5000 Córdoba, Argentina.
2
From the Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905.
3
Instituto de Investigaciones en Ciencias de la Salud, Consejo Nacional de Investigaciones Científicas y Técnicas and Facultad de Ciencias Médicas-Universidad Nacional de Córdoba, Ciudad Universitaria, 5000 Córdoba, Argentina.
4
Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University, Center for Life Nano Science at Sapienza, Istituto Italiano di Tecnologia, 00161 Rome, Italy.
5
Department of Molecular Medicine, Sapienza University, Pasteur Institute/Cenci-Bolognetti Foundation, 00161 Rome, Italy, and.
6
Gastroenterology and Gastrointestinal Oncology, University Medical Center Göttingen, 37075 Göttingen, Germany.
7
From the Schulze Center for Novel Therapeutics, Division of Oncology Research, Mayo Clinic, Rochester, Minnesota 55905, fernandezzapico.martin@mayo.edu.

Abstract

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. We demonstrated that down-regulation of the transcription factor glioma-associated 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 that AA represses 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 AA-induced 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.

KEYWORDS:

GLI1; arachidonic acid (AA) (ARA); cancer; cell death; polyunsaturated fatty acid (PUFA); transcription factor

PMID:
26601952
PMCID:
PMC4722469
DOI:
10.1074/jbc.M115.691972
[Indexed for MEDLINE]
Free PMC Article

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