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.

• Authors: Pramod Darvin, Youn Hee Joung, Dong Young Kang, Nipin Sp, Hyo Joo Byun, Tae Sook Hwang, Hema Sasidharakurup, Chi Ho Lee, Kwang Hyun Cho, Kyung Do Park, Hak Kyo Lee, Young Mok Yang
• Journal: Journal of cellular and molecular medicine (J Cell Mol Med) Vol. 21 Issue 4 Pg. 720-734 (04 2017) ISSN: 1582-4934 [Electronic] England
• PMID: 27862996 (Publication Type: Journal Article)
• Copyright: © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

Chemical References

• Cyclin-Dependent Kinase Inhibitor p21
• Quinazolines
• STAT1 Transcription Factor
• STAT3 Transcription Factor
• Tannins
• Tamoxifen
• ErbB Receptors
• p38 Mitogen-Activated Protein Kinases
• Gefitinib

Topics

• Apoptosis (drug effects)
• Breast Neoplasms (metabolism, pathology)
• Cell Line, Tumor
• Cell Nucleus (drug effects, metabolism)
• Cyclin-Dependent Kinase Inhibitor p21 (metabolism)
• Drug Synergism
• ErbB Receptors (metabolism)
• Female
• G1 Phase Cell Cycle Checkpoints (drug effects)
• Gefitinib
• Humans
• Phosphorylation (drug effects)
• Promoter Regions, Genetic (genetics)
• Protein Binding (drug effects)
• Protein Transport (drug effects)
• Quinazolines (pharmacology)
• STAT1 Transcription Factor (metabolism)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Tamoxifen (pharmacology)
• Tannins (pharmacology)
• p38 Mitogen-Activated Protein Kinases (metabolism)