Tannic acid inhibits EGFR / STAT 1/3 and enhances p38/ STAT 1 signalling axis in breast cancer cells

• Published in: Journal of cellular and molecular medicine 2017-04, Vol.21 (4), p.720-734
• Main Authors: Darvin, Pramod, Joung, Youn Hee, Kang, Dong Young, Sp, Nipin, Byun, Hyo Joo, Hwang, Tae Sook, Sasidharakurup, Hema, Lee, Chi Ho, Cho, Kwang Hyun, Park, Kyung Do, Lee, Hak Kyo, Yang, Young Mok
• Format: Article
• Language: English
• Subjects: Acids; Apoptosis; Breast cancer; Breast carcinoma; Cell cycle; Cell growth; Cyclin-dependent kinase inhibitor p21; Cytochrome; Cytochrome c; Deoxyribonucleic acid; DNA; Drug dosages; Epidermal growth factor; Epidermal growth factor receptors; Experiments; Inhibition; Janus kinase 2; Kinases; Localization; Metastasis; Mitochondria; p53 Protein; Phosphorylation; Polyphenols; Protein-serine kinase; Proteins; Signal transduction; Stat1 protein; Stat3 protein; Tannic acid; Tumor suppressor genes; Tumors; Tyrosine
• ISSN: 1582-1838; 1582-4934
• DOI: 10.1111/jcmm.13015

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 STAT 1 ser727 phosphorylation via upstream serine kinase p38. This STAT 1 ser727 phosphorylation enhanced the DNA ‐binding activity of STAT 1 and in turn enhanced expression of p21 Waf1/Cip1 . However, TA binds to EGF ‐R and inhibits the tyrosine phosphorylation of both STAT 1 and STAT 3. This inhibition leads to the inhibition of STAT 3/ BCL ‐2 DNA ‐binding activity. As a result, the expression and mitochondrial localization of BC l‐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/ STAT 1/3 and P38/ STAT 1/p21 Waf1/Cip1 pathways and induce G1‐arrest and intrinsic apoptosis in breast carcinomas.