Inhibitory effects of tea on Erk and c-Jun phosphorylation in 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced lung tumors in A/J mice Free

737

We have reported that green tea effectively inhibits the development of lung tumors induced by NNK. In the present study, the effects of tea and its components on signal transduction pathways in NNK-induced lung tumorigenesis were investigated. All A/J mice treated with four doses of NNK (50 mg/kg, b.w., i.p.) once weekly for 4 weeks developed pulmonary adenomas by week 20. These mice were then administered 0.6% green tea, 0.4% epigallocatechin gallate (EGCG), or 0.044% caffeine through drinking water for 14 days. Immunohistochemical analysis showed that oral administration of green tea, EGCG, or caffeine significantly increased the apoptosis index (%) in lung adenomas as compared with NNK control group (0.38 ± 0.07, 0.30 ± 0.10, or 0.32 ± 0.07 vs. 0.14 ± 0.04, respectively), as measured by caspase 3-positive cells. EGCG and caffeine exhibited an inhibitory effect on vascular endothelial growth factor (VEGF) protein expression, showing a significantly decreased immunostaining score (0.84 ± 0.20 in EGCG group and 0.93 ± 0.02 in caffeine group vs. 1.47 ± 0.004 in NNK control group). Further analysis of phosphorylated c-Jun and phosphorylated Erk, as detected by phosphospecific antibodies immunohistochemically, showed that green tea, EGCG, or caffeine decreased the percentage of phospho-c-Jun positive-stained tumor cells (19.7 ± 6.8, 15.4 ± 6.3, and 4.7 ± 0.4 vs. 27.0 ± 7.4, p ≤ 0.01); and caffeine decreased the percentage of phospho-Erk positive-stained tumor cells (29.6 ± 7.6 vs. 16.1 ± 6.8, p ≤ 0.05) as compared with NNK control group. The results suggest that inhibition of c-Jun and Erk protein phosphorylation and subsequent induction of apoptosis and inhibition of VEGF by tea are the possible mechanisms for the inhibition of progression of lung tumors (Supported by NIH grant CA56673).