Nicotine has long been known to be the habit-forming drug in cigareette smoke, but recent research shows that nicotine also works with other components of smoke to promote cancer formation.

Nicotine connection Nicotine has long been known to be the habit-forming drug in cigarette smoke. However, recent research shows that nicotine also works with other components of smoke to promote cancer formation. Phillip Dennis, M.D., Ph.D., National Naval Medical Center: “So there are really three principle components of tobacco that have been identified that have adverse biological affects. Those include carcinogens, such as polyaromatic hydrocarbons and nitrosamines, as well as nicotine. The classic mechanism of lung carcinogenesis is based on the fact that carcinogens, when they are activated, end up causing DNA adducts and DNA damage. Many of the nitrosamines that are carcinogens are actually nicotine metabolites. But nonetheless, they are present in cigarette smoke. So that when a person smokes, there is exposure of epithelial cells to nicotine and nitrosamines. Nicotine and nitrosamines bind to nicotinic acetylcholine receptors, which have recently have been described on epithelial cells, which then transduce a signal to intracellular kinases that have profound cellular effects. So the serine-threonine kinase Akt has become a very hot molecular target in cancer biology. It is a kinase that is activated in response to many types of stimuli. Once active, Akt will phosphorylate many downstream substrates. Over 50 have been described to date, and some of them are very key players in control of cell cycle – such as P27 and P21, apoptosis – such as Bad and Mdm2, and protein translation such as Mtor and Tsc2. When Akt is activated by tobacco components in normal cells, it leads to the increased proliferation and survival of these cells. In addition, active Akt has been detected in the precursor to cancerous legions – bronchial displasia – from smokers. So the cumulative evidence suggests that Akt is an early and important target in lung cancer formation. Akt likely plays a role in lung tumorigenesis through the following mechanism. A smoker is exposed to nicotine which, although we know it has biologic effects outside of addiction, is the addictive component. This leads to exposure to the carcinogens that cause DNA damage. If DNA damage is not repaired, the cell has a crucial decision to make as to whether or not to undergo apoptosis. The role that Akt plays is probably in that crucial step. Because tobacco components activate Akt, which inhibits apoptosis, if Akt is active the apoptotic threshold is altered. And if apoptosis does not occur, it can lead to the accumulation of genetic changes – such as K-ras mutations, P53 mutations, etc – that are necessary for lung cancer formation.“

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