The effects of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone on the map kinase cascade in neoplastic and non-neoplastic pulmonary neuroendocrine cells

Small cell lung carcinoma (SCLC) is a highly malignant pulmonary neoplasm derived from a normally sparse population of pulmonary neuroendocrine cells (PNEC) that proliferate when exposed to tobacco associated carcinogens and hypoxic environments. Although the precise mechanism by which these mitogens result in cellular proliferation and subsequent transformation is not known, there has been abundant attention directed toward the mutagenic mechanisms of pulmonary carcinogenesis. However, a lack of specific mutations in many cases of SCLC fails to explain the inciting cause and the progression of this neoplasm. Therefore, a receptor mediated mechanism linking the specific tobacco derived nitrosamine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), to cellular proliferation via the MAP kinase signaling pathway has been proposed. Understanding the involvement of this pathway in the development of SCLC provides a unique target for potential chemopreventive and chemotherapeutic measures. NNK and hypoxia have a profound effect on the MAP kinase signal transduction pathway and nuclear phospho-protein activation. This intracellular signaling cascade has been shown to play a critical role in the regulation of cell cycle events and cell proliferation. Exposure of both neoplastic and non-neoplastic PNECs to NNK results in the activation of the protein kinases, Raf-1 and MAPK 1\2, within the MAP kinase signaling pathway, as demonstrated by immunoblotting techniques and in vitro kinase assays. Additionally, NNK stimulates the phosphorylation of specific nuclear proteins involved in subsequent cell cycle regulation. These induced levels of activation can be significantly attenuated by various inhibitors that act on the receptor or on specific protein kinase domains. Based on these findings, the tobacco specific carcinogen, NNK, reliably induces an activating signal on the MAP kinase cascade and its downstream early gene nuclear transcripts. This, in turn, is believed to result in the proliferation of the neoplastic and non-neoplastic pulmonary neuroendocrine cells. Future investigations will be done to link these NNK induced intracellular signaling events with specific cell cycle responses.