title: 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/Cip1pathways and induce G1-arrest and intrinsic apoptosis in breast carcinomas.
authors.affiliation: Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul, South Korea.
authors.forename: Pramod
authors.initials: P
authors.lastname: Darvin
authors.affiliation: Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul, South Korea.
authors.forename: Youn Hee
authors.initials: YH
authors.lastname: Joung
authors.affiliation: Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul, South Korea.
authors.forename: Dong Young
authors.initials: DY
authors.lastname: Kang
authors.affiliation: Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul, South Korea.
authors.forename: Nipin
authors.initials: N
authors.lastname: Sp
authors.affiliation: Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul, South Korea.
authors.forename: Hyo Joo
authors.initials: HJ
authors.lastname: Byun
authors.affiliation: Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul, South Korea.
authors.forename: Tae Sook
authors.initials: TS
authors.lastname: Hwang
authors.affiliation: Amrita School of Biotechnology, Amrita Vishwa Vidyapeetham (Amrita University), Kollam, India.
authors.forename: Hema
authors.initials: H
authors.lastname: Sasidharakurup
authors.affiliation: Department of Food Science and Biotechnology of Animal Resources, Konkuk University, Seoul, South Korea.
authors.forename: Chi Ho
authors.initials: CH
authors.lastname: Lee
authors.affiliation: National Institute of Animal Science, RDA, Cheonan, South Korea.
authors.forename: Kwang Hyun
authors.initials: KH
authors.lastname: Cho
authors.affiliation: Department of Animal Biotechnology, Chonbuk National University, Jeonju, South Korea.
authors.forename: Kyung Do
authors.initials: KD
authors.lastname: Park
authors.affiliation: Department of Animal Biotechnology, Chonbuk National University, Jeonju, South Korea.
authors.forename: Hak Kyo
authors.initials: HK
authors.lastname: Lee
authors.affiliation: Department of Pathology, School of Medicine, Institute of Biomedical Science and Technology, Konkuk University, Seoul, South Korea.
authors.forename: Young Mok
authors.initials: YM
authors.lastname: Yang
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D000077156:Gefitinib; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D011799:Quinazolines / Q000494:pharmacology; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013629:Tamoxifen / Q000494:pharmacology; D013634:Tannins / Q000494:pharmacology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
chemical_list: D050759:Cyclin-Dependent Kinase Inhibitor p21; D011799:Quinazolines; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; D013634:Tannins; D013629:Tamoxifen; D066246:ErbB Receptors; D048051:p38 Mitogen-Activated Protein Kinases; D000077156:Gefitinib
keywords: G1 arrest; STAT1 ser727; STAT3/BCl-2 mitochondrial apoptosis; p38/STAT1; tannic acid