4-(Methylnitrosamino)-1-(3-Pyridyl)-1-Butanone Promotes Esophageal Squamous Cell Carcinoma Growth via Beta-Adrenoceptors In Vitro and In Vivo

Cigarette smoke is a risk factor for esophageal squamous cell carcinoma (ESCC). It contains several carcinogens known to initiate and promote tumorigenesis as well as metastasis. The nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is one of the strongest carcinogens in tobacco and our previous studies have shown its proliferation-promoting role in the progression of ESCC. Recently, NNK was identified as an agonist for both beta1- and beta2-adrenoceptors. Thus, we hypothesized that the cancer-promoting effect of NNK was likely mediated through beta-adrenoceptors in ESCC. Therefore, we investigated the comprehensive role of NNK in ESCC in vitro and in vivo, and found that NNK promoted many oncogenic features including ESCC cell proliferation and xenograft tumor growth as well as ESCC cell migration and invasion. Western blotting showed that NNK induced significant up-regulation of phosphorylated ERK1/2, cyclin D1, Bcl-2, and vascular endothelial growth factor as well as down-regulation of Bax. Importantly, the oncogenic effects of NNK in ESCC and the altered protein expression were reversed to some extent by down-regulation of beta1- and beta2-adrenoceptors with the beta2-adrenoceptor showing a greater rescue effect. Taken together, our in vitro and in vivo results demonstrate that NNK plays an oncogenic role in ESCC through beta-adrenoceptors. Furthermore, beta2-adrenoceptor might play a more important role in this process. Our findings might provide a chemoprevention and therapy strategy for cigarette smoke-related ESCC carcinogenesis.