MicroRNA profile of polyunsaturated fatty acid treated glioma cells reveal apoptosis-specific expression changes

Faragó, Nóra; Feher, L; Kitajka, Klára; Das, Undurti N.; Puskás, László G.

doi:10.1186/1476-511x-10-173

Cited by 62 publications

(52 citation statements)

References 23 publications

(21 reference statements)

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“…Faragó et al demonstrated the effect of PUFAs, including DHA, on the involvement of the microRNA profile in apoptosis-specific changes in treated glioblastoma cell lines. 8 In their study, these investigators observed similar findings with the administration of temozolomide alone.…”

supporting

confidence: 72%

Enhanced anticancer properties of lomustine in conjunction with docosahexaenoic acid in glioblastoma cell lines

Harvey

Saaddatzadeh

et al. 2015

JNS

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abbreviatioNs BCA = bicinchoninic acid; CSC = Cell Systems Corporation; DHA = docosahexaenoic acid; DMEM = Dulbecco's modified essential medium; DPA = docosapentaenoic acid; ED 50 = median effective dose; EMEM = Eagle's minimum essential medium; EPA = eicosapentaenoic acid; FBS = fetal bovine serum; HBMEC = human brain microvascular endothelial cell; HCCMEC = human cerebral cortex microvascular endothelial cell; OD = optical density; PARP = poly (ADP-ribose) polymerase; PBS = phosphate-buffered saline; PUFA = polyunsaturated fatty acid. obJect Glioblastoma is a rapidly infiltrating tumor that consistently rematerializes despite various forms of aggressive treatment. Brain tumors are commonly treated with alkylating drugs, such as lomustine, which are chemotherapeutic agents. Use of these drugs, however, is associated with serious side effects. To reduce the side effects, one approach is to combine lower doses of chemotherapeutic drugs with other nontoxic anticancer agents. In this study, using glioblastoma cell lines, the authors investigated the anticancer effects of lomustine, alone and in combination with docosahexaenoic acid (DHA), an omega-3 polyunsaturated fatty acid normally abundant in the brain and known for its anticancer potential. methods Cells were cultured from 3 human-derived tumor cell lines (U87-MG, DB029, and MHBT161) and supplemented with either DHA or lomustine to determine the growth inhibitory potential using WST-1, a mitochondrial functional indicator. Human-derived cerebral cortex microvascular endothelial cells served as a normal phenotypic control. Cellular incorporation of DHA was analyzed by gas chromatography. Using flow cytometric analysis, the DHA and/or lomustine effect on induction of apoptosis and/or necrosis was quantified; subsequently, the DHA and lomustine effect on cell cycle progression was also assessed. Western blot analysis confirmed the role of downstream cellular targets. results U87-MG growth was inhibited with the supplementation of either DHA (ED 50 68.3 mM) or lomustine (ED 50 68.1 mM); however, growth inhibition was enhanced when U87-MG cells were administered equimolar doses of each compound, resulting in nearly total growth inhibition at 50 mM. Gas chromatography analysis of the fatty acid profile in DHA-supplemented U87-MG cells resulted in a linear dose-dependent increase in DHA incorporation (< 60 mM). The combination of DHA and lomustine potently induced U87-MG apoptosis and necrosis as indicated by flow cytometric analysis. Activation of caspase-3 and poly (ADP-ribose) polymerase (PARP) was evident in lomustine-treated U87-MG cells, although this activation did not appear to be dependent on DHA supplementation. Additionally, lomustine-treated cells' growth arrested in the G 2 /M cell cycle stage, regardless of the presence of DHA. Similar to the U87-MG observations, the combination of DHA and lomustine resulted in growth inhibition of 2 additional human-derived glioblastoma cell lines, DB029 and MHBT161. Importantly, in primary human-derived cerebral corte...

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supporting

confidence: 72%

Enhanced anticancer properties of lomustine in conjunction with docosahexaenoic acid in glioblastoma cell lines

Harvey

Saaddatzadeh

et al. 2015

JNS

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“…Therefore, although the two conditions shared a similar miRNA expression pattern, 69 miRNAs (51 upregulated and 18 downregulated in aMEM) deviated from linearity with 4-fold or higher differential expression (Table 3). Of note, two miRNA that were demonstrated to be repressed by different PUFA (including linoleic acid) in glioma cells (miR-143 and miR-125b; Faragó et al, 2011) showed an identical pattern in CBMSC grown in SPE-IV, that was able to reduce both miR-143 (16.80 fold) and miR-125b (4.23 fold) with respect to aMEM. Moreover, our results are also in agreement with those obtained in the work of Parra and colleagues that showed, upon conjugated linoleic acid treatment in mice, repression for miR-143 and induction of miR-221/222 as we observed in SPE-IV (5.55 and 14.29 fold) (Parra et al, 2010).…”

Section: Identification Of Unique Mirna Signatures and Target Analysismentioning

confidence: 93%

“…Then we decided to investigate on a molecular level the macroscopic changes previously described since differences in medium supplements, as fatty acids, have been recently shown to modulate different parameters like miRNA expression (Parra et al, 2010;Faragó et al, 2011). So, we performed a miRNA expression profiling monitoring the amount of 704 mature miRNA using qRT-PCR arrays.…”

Section: Identification Of Mirna Expression Profiles In Amem and Spe-mentioning

confidence: 99%

Diet composition transiently modulates proliferative and potency features of human cord blood-derived mesenchymal stem cells

Ragni

Parazzi

Crosti

et al. 2014

The International Journal of Biochemistry & Cell Biology

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“…We showed that AA reduces the expression of these genes by regulating their promoter activity in a transcriptional manner. Several studies have demonstrated that AA reduces the expression of apoptosis-related proteins, including the known antiapoptotic protein BCL2 (20,63,64). However, no studies have linked AA or other PUFAs to the antiapoptotic genes BFL1/A1 and 4-1BB.…”

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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MicroRNA profile of polyunsaturated fatty acid treated glioma cells reveal apoptosis-specific expression changes

Cited by 62 publications

References 23 publications

Enhanced anticancer properties of lomustine in conjunction with docosahexaenoic acid in glioblastoma cell lines

Enhanced anticancer properties of lomustine in conjunction with docosahexaenoic acid in glioblastoma cell lines

Diet composition transiently modulates proliferative and potency features of human cord blood-derived mesenchymal stem cells

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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