urine. Signaling pathways Once NNK is activated, NNK initiates a cascade of signaling pathways (for example ERK1/2, NFκB, PI3K/Akt, MAPK, FasL, K-ras), resulting in uncontrolled cellular proliferation and tumorigenesis. NNK activates µ en m-calpain kinase which induce lung metastasis via the ERK1/2 pathway. This pathway upregulate cellular myelocytomatosis (c-Myc) and B cell leukemia/lymphoma 2 (Bcl2) in which the two oncoprotein are involved in cellular proliferation, transformation and apoptosis. Also does NNK promotes cell survival via phosphorylation with cooperation of c-Myc and Bcl2 causing cellular migration, invasion and uncontrolled proliferation. The ERK1/2 pathway also phosphorylate NFκB causing an upregulation of cyclin D1, a G1 phase regulator protein. When NNK is present it directly involves cellular survival dependent on NFκB. Further studies are needed to better understand NNK cellular pathways of NFκB. The phosphoinositide 3-kinase (PI3K/Akt) pathway is also an important contributor to NNK-induced cellular transformations and metastasis. This process ensures the proliferation and survival of tumorigenic cells. The ERK1/2 and Akt pathways show consequential changes in levels of protein expression as a result of NNK-activation in the cells, but further research is needed to fully understand the mechanism of NNK-activated pathways. Pathology Toxicity NNK is known as a mutagen, which means it causes polymorphisms in the human genome. Studies showed that NNK induced gene polymorphisms in cells that involve in cell growth, proliferation and differentiation. There are multiple NNK dependent routes that involve cell proliferation. One example is the cell route that coordinates the downregulation of retinoic acid receptor beta (RAR-β). Studies showed that with a 100 mg/kg dose of NNK, several point mutations were formed in the RAR-β gene, inducing tumorigenesis in the lungs. Other genes affected by NNK include sulfotransferase 1A1 (SULT1A1), transforming growth factor beta (TGF-β), and angiotensin II (AT2). NNK plays a very important role in gene silencing, modification, and functional disruption which induce carcinogenesis. Inhibition Chemical compounds derived from cruciferous vegetables and EGCG inhibit lung tumorigenesis by NNK in animal models. Whether these effects have any relevance to human health is unknown and is a subject of ongoing research. See also Toxification References External links MSDS Nitrosamines 3-Pyridyl compounds IARC Group 1 carcinogens Aromatic ketones