The calcineurin/NFAT signaling pathway: A NOVEL therapeutic target in leukemia and solid tumors

Medyouf, Hind; Ghysdael, Jacques

doi:10.4161/cc.7.3.5357

Cited by 101 publications

(93 citation statements)

References 75 publications

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“…We also show that GLI1 repression by AA is blocked by CsA, an inhibitor of calcineurin. This result suggests that calcineurin plays a role in the signal cascade initiated by AA treatment in our studies, which is consistent with the known role of calcineurin in the activation of NFATc1 (46,47). However, further studies are needed to determine the precise mechanisms of NFATc1 activation by AA.…”

Section: Discussionsupporting

confidence: 78%

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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

Comba

Almada

Tolosa

et al. 2016

Journal of Biological Chemistry

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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 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 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 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.

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Section: Discussionsupporting

confidence: 78%

“…NFATc1 activation is often mediated by the phosphatase calcineurin (46,47). Thus, we next investigated the involvement of calcineurin in the AA-initiated repression of GLI1 expression.…”

Section: Bcl2 Bfl1/a1 and 4-1bb Are Direct Targets Of Gli1-bioinformentioning

confidence: 99%

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

Comba

Almada

Tolosa

et al. 2016

Journal of Biological Chemistry

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“…Mice expressing an NFAT allele with increased affinity for calcineurin exhibit developmental abnormalities (8). Alterations in calcineurin activity have been linked to multiple human diseases including cardiac hypertrophy (9,10), cancer (11,12), and neurodegeneration (13). Inhibition of calcineurin phosphatase activity underlies the therapeutic action of the immunosuppressants tacrolimus and cyclosporine A, which have been extensively administered to patients to prevent organ transplant rejection (14).…”

Section: Camentioning

confidence: 99%

Regulatory Subunit Myristoylation Antagonizes Calcineurin Phosphatase Activation in Yeast

Connolly

Kingsbury

2012

Journal of Biological Chemistry

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“…82 An immunohistological screening of NFATc1 in a large series of lymphomas showed that NFATc1 is expressed in almost all categories of T-NHL studied. 84 Also, nuclear localization of NFATc1 or dephosphorylation of both NFATc1 and NFATc2 are revealed by western blot in PTCL.…”

Section: Calcineurin/nf Of Activated T Cells Pathwaymentioning

confidence: 99%

“…82 Caleincurin is composed of a catalytic (CnA) and a regulatory (CnB) subunit. Increase in intracellular calcium results in calcium-dependent binding of calmodulin to calcineurin, thus relieving the inhibitory activity of the autoinhibitory domain on CnA and leading to the dephosphorylation, nuclear translocation, and consequent activation of calcineurin substrates NFAT.…”

Section: Calcineurin/nf Of Activated T Cells Pathwaymentioning

confidence: 99%

Targeted therapy in T-cell malignancies: dysregulation of the cellular signaling pathways

2009

Leukemia

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The calcineurin/NFAT signaling pathway: A NOVEL therapeutic target in leukemia and solid tumors

Cited by 101 publications

References 75 publications

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

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

Regulatory Subunit Myristoylation Antagonizes Calcineurin Phosphatase Activation in Yeast

Targeted therapy in T-cell malignancies: dysregulation of the cellular signaling pathways

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