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.
Highlights
Breast cancer (BCa) is a major cause of cancer-related death with the highest prevalence than other cancers worldwide [1]
Inhibition of Jak2 using AG490 did not alter the level of STAT1 ser727 phosphorylation, but it partially recovered tannic acid (TA)-induced STAT1 tyr701 phosphorylation and G1 arrest
P38 activation is involved in STAT1 transcriptional functions, as DNA-binding activity was inhibited upon p38 inhibition
Summary
Breast cancer (BCa) is a major cause of cancer-related death with the highest prevalence than other cancers worldwide [1]. Polyphenols are plant-derived secondary metabolites, recognized for their anti-mutagenic, anti-oxidant and anti-cancer effects [2, 3]. Tannins are water-soluble polyphenols widely distributed in the plant kingdom, including food grains and fruits [4]. Tannic acid (TA) is a hydrolysable tannin that yields glucose and Tannic acid has been reported to have high tyrosine kinase inhibition capacity. Tyrosine kinase activity of TA is observed with inhibition of CXCL12 (SDF-1a)/CXCR4. In this case, TA served as an antiangiogenic factor [4]. TA showed inhibition on serine/threonine kinases including cAMP-dependent protein kinases, protein kinase c and mitogen activated protein kinases [10]
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