Dual Effect of Taxifolin on ZEB2 Cancer Signaling in HepG2 Cells

Abstract

Polyphenols, secondary metabolites of plants, exhibit different anti-cancer and cytoprotective properties such as anti-radical, anti-angiogenic, anti-inflammation, or cardioprotective. Some of these activities could be linked to modulation of miRNAs expression. MiRNAs play an important role in posttranscriptional regulation of their target genes that could be important within cell signalling or preservation of cell homeostasis, e.g., cell survival/apoptosis. We evaluated the influence of a non-toxic concentration of taxifolin and quercetin on the expression of majority human miRNAs via Affymetrix GeneChip™ miRNA 3.0 Array. For the evaluation we used two cell models corresponding to liver tissue, Hep G2 and primary human hepatocytes. The array analysis identified four miRNAs, miR-153, miR-204, miR-211, and miR-377-3p, with reduced expression after taxifolin treatment. All of these miRNAs are linked to modulation of ZEB2 expression in various models. Indeed, ZEB2 protein displayed upregulation after taxifolin treatment in a dose dependent manner. However, the modulation did not lead to epithelial mesenchymal transition. Our data show that taxifolin inhibits Akt phosphorylation, thereby diminishing ZEB2 signalling that could trigger carcinogenesis. We conclude that biological activity of taxifolin may have ambiguous or even contradictory outcomes because of non-specific effect on the cell.

The role of flavonoids in the regulation of epithelial‐mesenchymal transition in cancer: A review on targeting signaling pathways and metastasis

“…The inhibition of AKT phosphorylation by taxifolin counteracted possible EMT effects originated from ZEB2 upregulation. 151 In hepatocellular carcinoma cells, Huh7 cells, upstream phosphorylated AKT and GSK-3β were downregulated in puerarin-treated cells. 152 Lung cancer: the levels of p-AKT and p-GSK-3β, but had no significant effect on ERK phosphorylation.…”

“…137 Also in HepG2 cells, taxifolin inhibited AKT phosphorylation, the latter being a decisive signal for vimentin downregulation. 151 To confirm this hypothesis, it was found that the AKT inhibitor GSK690693 showed correlation between AKT activity and vimentin expression.…”

“…Truncated β-catenin expression was, in turn, unaffected. 151 In female Swiss albino mice with induced liver and tongue carcinogenesis, β-catenin and EGFRmediated signaling processes were activated during carcinogenesis. Importantly, in this study EGCG reduced the expression of β-catenin mRNA, as well as cytosolic and nuclear protein.…”

Ameliorative effect of taxifolin on gentamicin-induced ototoxicity via down-regulation of apoptotic pathways in mouse cochlear UB/OC-2 cells

“…27 Taxifolin has been shown to possess anticancer properties by diminishing ZEB signaling through AKT. 28 It has also been shown that taxifolin treatment can significantly attenuate rotenone-induced renal dysfunction. 29…”

“…27 Taxifolin has been shown to possess anticancer properties by diminishing ZEB signaling through AKT. 28 It has also been shown that taxifolin treatment can significantly attenuate rotenone-induced renal dysfunction. 29 The combination of different drugs could reduce ototoxic side effects without the cost of developing a new antibiotic or compromising antimicrobial activity.…”