Tannic acid inhibits EGFR/STAT1/3 and enhances p38/STAT1 signalling axis in breast cancer cells

Abstract

Tannic acid (TA), a naturally occurring polyphenol, is a potent anti‐oxidant with anti‐proliferative effects on multiple cancers. However, its ability to modulate gene‐specific expression of tumour suppressor genes and oncogenes has not been assessed. This work investigates the mechanism of TA to regulate canonical and non‐canonical STAT pathways to impose the gene‐specific induction of G1‐arrest and apoptosis. Regardless of the p53 status and membrane receptors, TA induced G1‐arrest and apoptosis in breast cancer cells. Tannic acid distinctly modulated both canonical and non‐canonical STAT pathways, each with a specific role in TA‐induced anti‐cancer effects. Tannic acid enhanced STAT1 ser727 phosphorylation via upstream serine kinase p38. This STAT1 ser727 phosphorylation enhanced the DNA‐binding activity of STAT1 and in turn enhanced expression of p21Waf1/Cip1. However, TA binds to EGF‐R and inhibits the tyrosine phosphorylation of both STAT1 and STAT3. This inhibition leads to the inhibition of STAT3/BCL‐2 DNA‐binding activity. As a result, the expression and mitochondrial localization of BCl‐2 are declined. This altered expression and localization of mitochondrial anti‐pore factors resulted in the release of cytochrome c and the activation of intrinsic apoptosis cascade involving caspases. Taken together, our results suggest that TA modulates EGF‐R/Jak2/STAT1/3 and P38/STAT1/p21Waf1/Cip1 pathways and induce G1‐arrest and intrinsic apoptosis in breast carcinomas.

Effects of polyphenols on doxorubicin‐induced oral keratinocyte cytotoxicity and anticancer potency against oral cancer cells

“…Aside from the different time pattern, cell cycle modulatory effect of polyphenols might be another mechanism for their different mode of action. Studies suggested that EGCG and TA on cell cycle distribution are dependent on concentration, cell cycle states, and possibly cell types . EGCG has been reported to induce G1 arrest in MCF‐7 cells through modulating the expression of cell cycle regulators including Cdk2 and Cdk4 as well as mediating the induction of Cdk inhibitor p21 and p27 .…”

“…Studies suggested that EGCG and TA on cell cycle distribution are dependent on concentration, cell cycle states, and possibly cell types. [19][20][21] EGCG has been reported to induce G1 arrest in MCF-7 cells through modulating the expression of cell cycle regulators including Cdk2 and Cdk4 as well as mediating the induction of Cdk inhibitor p21 and p27. 22 In contrast, TA induced G1 arrest and mitochondrial apoptosis in YD-38 gingival cancer cells by inhibiting the Jak2/STAT3 signaling pathway.…”

Tannic Acid: Specific Form of Tannins in Cancer Chemoprevention and Therapy-Old and New Applications

“…Booth et al [32] performed a series of experiments in which ER-positive breast cancer cells, MCF7, and triple negative (ER − , PR − , HER2 − ) MDA-MB-231 along with nontumorigenic MCF10A were exposed to TA-cross-linked collagen type I beads. Growing cells remodeled collagen and released TA into surrounding medium leading to caspasemediated apoptosis.…”

“…It was found that TA modulates the EGFR/Jak2/STAT3 pathway, inducing mitochondrial apoptosis in breast cancer cells lines: MCF-7, T47D, SK-BR 3, and MDA-MB-231. Moreover, both the enhancement of STAT1 ser727 phosphorylation and the inhibition of STAT1 tyr701 phosphorylation were discovered as the key factors leading to G1 arrest upon TA treatment [32].…”

Telomerase Inhibitors from Natural Products and Their Anticancer Potential

“…Tannic acid (TA) is a naturally occurring polyphenol found in red wine, grapes, beans, tea, coffee, nuts and various vegetables and fruits. Several studies have shown that TA has a potential activity in cancer prevention [ 199 , 200 , 201 , 202 , 203 , 204 ]. Cosan et al [ 168 ] have investigated the impacts of TA on telomerase activity, cell viability, number of cells and DNA fragmentation in human breast (MCF-7) and human colon cancer (CaCo-2) cell lines.…”