Gramine attenuates EGFR-mediated inflammation and cell proliferation in oral carcinogenesis via regulation of NF-κB and STAT3 signaling

Gramine, a natural indole alkaloid found in Hordeum vulgare has been possesses anti-mutagenic properties. The aim of the present study was to evaluate the effect of gramine on inflammation and proliferation in 7,12-dimethylbenz[a] anthracene(DMBA)-induced hamster buccal pouch (HBP) carcinogenesis. Epidermal growth factor receptor (EGFR) tyrosine kinase phosphorylation trigged PI3K/Akt/mTOR and JAK signaling that activates NF-kappa B and STAT3. In contrast, gramine suppressed EGFR tyrosine kinase phosphorylation and simultaneously inhibiting PI3K/Akt/mTOR and JAK phosphorylation, thereby blockage NF-kappa B and STAT3 nuclear translocation. Attenuation of these oncogenic signals leads to downregulated iNOS, COX-2, TNF-alpha, IL-6, cyclin D1 and PCNA protein expressions. In addition, gramine enhanced the expression of the tumor suppressors p53, p21((WAF1/CIP1)) and Gsk-3 beta by inhibiting MDM2. These results suggested that gramine exhibited anti-inflammation and anti-proliferation effects via suppressed EGFR/PI3K/Akt/mTOR/IKK/NF-kappa B and JAK/STAT3 signaling pathways.