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Crambescin C1 Exerts a Cytoprotective Effect on HepG2 Cells through Metallothionein Induction.

Roel M, Rubiolo JA, Ternon E, Thomas OP, Vieytes MR, Botana LM - Mar Drugs (2015)

Bottom Line: Some of the biological effects of crambescidins have been previously reported while crambescins have undergone little study.Taking this into account, we performed comparative transcriptome analysis to examine the effect of crambescin-C1 (CC1) on human tumor hepatocarcinoma cells HepG2 followed by validation experiments to confirm its predicted biological activities.The findings presented here provide the first detailed approach regarding the different effects of crambescins on tumor cells and provide a basis for future studies on other possible cellular mechanisms related to these bioactivities.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela (USC), Campus Lugo, 27002 Lugo, Spain. maria.roel@usc.es.

ABSTRACT
The Mediterranean marine sponge Crambe crambe is the source of two families of guanidine alkaloids known as crambescins and crambescidins. Some of the biological effects of crambescidins have been previously reported while crambescins have undergone little study. Taking this into account, we performed comparative transcriptome analysis to examine the effect of crambescin-C1 (CC1) on human tumor hepatocarcinoma cells HepG2 followed by validation experiments to confirm its predicted biological activities. We report herein that, while crambescin-A1 has a minor effect on these cells, CC1 protects them against oxidative injury by means of metallothionein induction even at low concentrations. Additionally, at high doses, CC1 arrests the HepG2 cell cycle in G0/G1 and thus inhibits tumor cell proliferation. The findings presented here provide the first detailed approach regarding the different effects of crambescins on tumor cells and provide a basis for future studies on other possible cellular mechanisms related to these bioactivities.

No MeSH data available.


Related in: MedlinePlus

(A) Venn diagram for the down-regulated mRNAs in HepG2 cells treated with 5 and 10 μM crambescin C1 (CC1) for 24 h; (B) Pathways repressed by CC1 at both concentrations tested, as determined by Kyoto Encyclopedia of Genes and Genomes (KEGGS) pathways; (C) Pathways repressed by 10 μM CC1 as determined by KEGGS pathways; (D) Pathways repressed by 10 μM CC1 as determined by KEGGS pathways. In all cases an enrichment p-value from modified Fisher’s Exact test (EASE Score) <0.05 was selected for significant pathway identification; (E) Graph showing the relative increment of metallothionein expression in CC1 treated cultures respect to controls. Shown increments were identified as significant after microarray analysis, p < 0.05, n = 3.
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marinedrugs-13-04633-f004: (A) Venn diagram for the down-regulated mRNAs in HepG2 cells treated with 5 and 10 μM crambescin C1 (CC1) for 24 h; (B) Pathways repressed by CC1 at both concentrations tested, as determined by Kyoto Encyclopedia of Genes and Genomes (KEGGS) pathways; (C) Pathways repressed by 10 μM CC1 as determined by KEGGS pathways; (D) Pathways repressed by 10 μM CC1 as determined by KEGGS pathways. In all cases an enrichment p-value from modified Fisher’s Exact test (EASE Score) <0.05 was selected for significant pathway identification; (E) Graph showing the relative increment of metallothionein expression in CC1 treated cultures respect to controls. Shown increments were identified as significant after microarray analysis, p < 0.05, n = 3.

Mentions: To compare gene expression patterns of repressed genes, a Venn diagram was used since the lowest concentration induced few genes when compared to the highest one. Both concentrations repressed 163 genes while more than 500 genes were independently repressed by each of them (Figure 4A). According to Keggs pathway analysis, shared genes with the highest enrichment scores are involved in drug and xenobiotic metabolism. Other processes like lipid, retinoid acid, tyrosine, glutathione, linoleic acid, bile acid, and steroid hormone metabolism and/or biosynthesis, although significant, presented lower enrichment scores (Figure 4B). Genes down-regulated by 10 μM CC1, which were not affected in cells treated with 5 μM CC1, are tied to cell cycle control and progression, DNA replication and cellular adhesion (Figure 4C). Genes exclusively down-regulated by 5 μM CC1 are involved in drug, xenobiotic, sugar and lipids metabolisms (Figure 3D). Even though 5 μM CC1 treatment induced few genes, it shared with the 10 μM treatment the induction of metallothioneins (MTs) 1 and 2 (Figure 4E). Therefore, induction of metallothionein expression was a widespread response of HepG2 cells to CC1 exposure.


Crambescin C1 Exerts a Cytoprotective Effect on HepG2 Cells through Metallothionein Induction.

Roel M, Rubiolo JA, Ternon E, Thomas OP, Vieytes MR, Botana LM - Mar Drugs (2015)

(A) Venn diagram for the down-regulated mRNAs in HepG2 cells treated with 5 and 10 μM crambescin C1 (CC1) for 24 h; (B) Pathways repressed by CC1 at both concentrations tested, as determined by Kyoto Encyclopedia of Genes and Genomes (KEGGS) pathways; (C) Pathways repressed by 10 μM CC1 as determined by KEGGS pathways; (D) Pathways repressed by 10 μM CC1 as determined by KEGGS pathways. In all cases an enrichment p-value from modified Fisher’s Exact test (EASE Score) <0.05 was selected for significant pathway identification; (E) Graph showing the relative increment of metallothionein expression in CC1 treated cultures respect to controls. Shown increments were identified as significant after microarray analysis, p < 0.05, n = 3.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4556997&req=5

marinedrugs-13-04633-f004: (A) Venn diagram for the down-regulated mRNAs in HepG2 cells treated with 5 and 10 μM crambescin C1 (CC1) for 24 h; (B) Pathways repressed by CC1 at both concentrations tested, as determined by Kyoto Encyclopedia of Genes and Genomes (KEGGS) pathways; (C) Pathways repressed by 10 μM CC1 as determined by KEGGS pathways; (D) Pathways repressed by 10 μM CC1 as determined by KEGGS pathways. In all cases an enrichment p-value from modified Fisher’s Exact test (EASE Score) <0.05 was selected for significant pathway identification; (E) Graph showing the relative increment of metallothionein expression in CC1 treated cultures respect to controls. Shown increments were identified as significant after microarray analysis, p < 0.05, n = 3.
Mentions: To compare gene expression patterns of repressed genes, a Venn diagram was used since the lowest concentration induced few genes when compared to the highest one. Both concentrations repressed 163 genes while more than 500 genes were independently repressed by each of them (Figure 4A). According to Keggs pathway analysis, shared genes with the highest enrichment scores are involved in drug and xenobiotic metabolism. Other processes like lipid, retinoid acid, tyrosine, glutathione, linoleic acid, bile acid, and steroid hormone metabolism and/or biosynthesis, although significant, presented lower enrichment scores (Figure 4B). Genes down-regulated by 10 μM CC1, which were not affected in cells treated with 5 μM CC1, are tied to cell cycle control and progression, DNA replication and cellular adhesion (Figure 4C). Genes exclusively down-regulated by 5 μM CC1 are involved in drug, xenobiotic, sugar and lipids metabolisms (Figure 3D). Even though 5 μM CC1 treatment induced few genes, it shared with the 10 μM treatment the induction of metallothioneins (MTs) 1 and 2 (Figure 4E). Therefore, induction of metallothionein expression was a widespread response of HepG2 cells to CC1 exposure.

Bottom Line: Some of the biological effects of crambescidins have been previously reported while crambescins have undergone little study.Taking this into account, we performed comparative transcriptome analysis to examine the effect of crambescin-C1 (CC1) on human tumor hepatocarcinoma cells HepG2 followed by validation experiments to confirm its predicted biological activities.The findings presented here provide the first detailed approach regarding the different effects of crambescins on tumor cells and provide a basis for future studies on other possible cellular mechanisms related to these bioactivities.

View Article: PubMed Central - PubMed

Affiliation: Departamento de Farmacología, Facultad de Veterinaria, Universidad de Santiago de Compostela (USC), Campus Lugo, 27002 Lugo, Spain. maria.roel@usc.es.

ABSTRACT
The Mediterranean marine sponge Crambe crambe is the source of two families of guanidine alkaloids known as crambescins and crambescidins. Some of the biological effects of crambescidins have been previously reported while crambescins have undergone little study. Taking this into account, we performed comparative transcriptome analysis to examine the effect of crambescin-C1 (CC1) on human tumor hepatocarcinoma cells HepG2 followed by validation experiments to confirm its predicted biological activities. We report herein that, while crambescin-A1 has a minor effect on these cells, CC1 protects them against oxidative injury by means of metallothionein induction even at low concentrations. Additionally, at high doses, CC1 arrests the HepG2 cell cycle in G0/G1 and thus inhibits tumor cell proliferation. The findings presented here provide the first detailed approach regarding the different effects of crambescins on tumor cells and provide a basis for future studies on other possible cellular mechanisms related to these bioactivities.

No MeSH data available.


Related in: MedlinePlus