Gamma-linolenic acid inhibits both tumour cell cycle progression and angiogenesis in the orthotopic C6 glioma model through changes in VEGF, Flt1, ERK1/2, MMP2, cyclin D1, pRb, p53 and p27 protein expression

Miyake, Juliano Andreoli; Benadiba, Marcel; Colquhoun, Alison

doi:10.1186/1476-511x-8-8

Cited by 45 publications

(28 citation statements)

References 33 publications

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“…tumor regression (8,9). In addition, clinical studies show that intracerebral injection of ␥-linolenic acid in patients with gliomas induces decreased tumor size (12,13).…”

Section: Discussionmentioning

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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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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“…tumor regression (8,9). In addition, clinical studies show that intracerebral injection of ␥-linolenic acid in patients with gliomas induces decreased tumor size (12,13).…”

Section: Discussionmentioning

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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“…The infusion rate was reduced to 0.5 µl/h, and the treatment consisted of 5 mM GLA infusion for a total of 14 days with the expectation that a higher dose for an extended period of time would improve tumour response to GLA [124]. The average tumour area of the GLA treated tumours was reduced by 75% in comparison with the control cerebrospinal fluidtreated tumours, and this was accompanied by a change in tumour fatty acid composition.…”

Section: Implications For Neuro-oncologymentioning

confidence: 99%

“…In a recently published study from the author's laboratory, GLA was applied directly into the tumour bed via osmotic pumps using the same orthotopic C6 glioma model used by Leaver et al [121,123,124]. The infusion rate was reduced to 0.5 µl/h, and the treatment consisted of 5 mM GLA infusion for a total of 14 days with the expectation that a higher dose for an extended period of time would improve tumour response to GLA [124].…”

Section: Implications For Neuro-oncologymentioning

confidence: 99%

Lipids, Mitochondria and Cell Death: Implications in Neuro-oncology

Colquhoun

2010

Mol Neurobiol

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Polyunsaturated fatty acids (PUFAs) are known to inhibit cell proliferation of many tumour types both in vitro and in vivo. Their capacity to interfere with cell proliferation has been linked to their induction of reactive oxygen species (ROS) production in tumour tissues leading to cell death through apoptosis. However, the exact mechanisms of action of PUFAs are far from clear, particularly in brain tumours. The loss of bound hexokinase from the mitochondrial voltage-dependent anion channel has been directly related to loss of protection from apoptosis, and PUFAs can induce this loss of bound hexokinase in tumour cells. Tumour cells overexpressing Akt activity, including gliomas, are sensitised to ROS damage by the Akt protein and may be good targets for chemotherapeutic agents, which produce ROS, such as PUFAs. Cardiolipin peroxidation may be an initial event in the release of cytochrome c from the mitochondria, and enriching cardiolipin with PUFA acyl chains may lead to increased peroxidation and therefore an increase in apoptosis. A better understanding of the metabolism of fatty acids and eicosanoids in primary brain tumours such as gliomas and their influence on energy balance will be fundamental to the possible targeting of mitochondria in tumour treatment.

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“…Then C6 glioma cell suspension was slowly injected through a Hamilton syringe and stereotaxic apparatus and the needle left in situ for 3-5 min before its removal. The coordinates were 1 mm in front of bregma, 3 mm lateral to the bregma, and 4.5 mm deep in the basal ganglia in the right brain, as previously described (Nicolau et al 1993;Ningaraj et al 2003;Miyake et al 2009). Fourteen days after the tumor implantation, the rats were prepared for injection.…”

Section: Animalsmentioning

confidence: 99%

Vascular Endothelial Growth Factor Increases Permeability of the Blood–Tumor Barrier via Caveolae-Mediated Transcellular Pathway

et al. 2010

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The first goal of this study was to determine the effect of vascular endothelial growth factor (VEGF) on permeability of the blood-tumor barrier (BTB). The second goal was to determine possible cellular mechanisms by which VEGF increases permeability of the BTB. In the rat C6 glioma model, the permeability of the BTB was significantly increased after VEGF injection at dose of 0.05 ng/g and reached its peak at 45 min. Meanwhile, we observed that the density of pinocytotic vesicles of brain microvascular endothelial cells (BMECs) in the BTB increased dramatically by transmission electron microscopy. The immunohistochemistry and western blot analysis revealed that the expression level of caveolae structure proteins caveolin-1 and caveolin-2 in BMECs was increased after VEGF injection, peaked at 45 min, and then decreased to the untreated level. The time peak of expression level of caveolin-1 and caveolin-2 was identical with the peak time of permeability of the BTB and the density of pinocytotic vesicles. All of these results strongly indicated that VEGF increased permeability of the BTB caused by enhancement of the density of pinocytotic vesicles, and the molecular mechanism might be associated with upregulated expression of caveolin-1 and caveolin-2.

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Gamma-linolenic acid inhibits both tumour cell cycle progression and angiogenesis in the orthotopic C6 glioma model through changes in VEGF, Flt1, ERK1/2, MMP2, cyclin D1, pRb, p53 and p27 protein expression

Cited by 45 publications

References 33 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

Lipids, Mitochondria and Cell Death: Implications in Neuro-oncology

Vascular Endothelial Growth Factor Increases Permeability of the Blood–Tumor Barrier via Caveolae-Mediated Transcellular Pathway

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