Black Tea Extract, via Modulation of TGF-β Pathway, Prevents Inorganic Arsenic-induced Development of Squamous Cell Carcinoma of the Skin in Swiss Albino Mice.

Abstract

Chronic exposure to inorganic arsenic (iAs) elevates reactive oxygen species (ROS) generation and up-regulates TGF-β signalling. This promotes induction of epithelial to mesenchymal transition (EMT) and causes the development of squamous cell carcinoma (SCC) of skin. Black tea is a popular beverage worldwide and an effective antioxidant. Chemopreventive potential of black tea extract (BTE) against iAs induced carcinogenicity has been explored here. The study aims to investigate the role of BTE in prevention of iAs-induced SCC of skin in Swiss albino mice via the modulation of TGF-β signalling and EMT. Mice were divided into (1) control, (2) iAs, (3) iAs+BTE, and (4) BTE groups and were administered iAs and BTE alone, or in combination for 330 days. Histological studies were performed to assess development of SCC. ROS generation was estimated by flowcytometry. Expression of TGF-β and downstream proteins belonging to suppressor of mothers against decapentaplegic (Smad), phosphoinositide-3-kinase (PI3K)-protein kinase B (AKT) and mitogen-activated protein kinase (MAPK) pathways was assessed by immunoblotting. Expression of EMT markers was evaluated by immunoblotting, immunohistochemistry and semi-quantitative reverse transcriptase-PCR. After 330 days of iAs treatment, development of invasive SCC of skin probably due to excess ROS generation, elevation of TGF-β, downregulation of the Smad pathway, upregulation of PI3K-AKT and MAPK signalling molecules and induction of EMT was observed. All these modulations were found to be reversed by BTE, which inhibits iAs induced SCC of skin by quenching excess ROS, promoting Smad mediated TGF-β signalling, downregulating signalling intermediates of PI3K-AKT and MAPK pathways and inhibiting EMT.