Background

What is a kinase?

Kinases are proteins that add phosphate groups to target proteins, either activating or inactivating them to cause a cellular response.

Figure 2. An example of a protein kinase cascade. The growth factor binds to its receptor and activates the phosphorylation of RAS, which then phosphorylates and activates Raf, which can then phosphorylate MEK and activate it, etc etc.

What is nicotine and how does it react in the human body?
Nicotine is an alkaloid found naturally in the leaves of tobacco plants (Meeker-O'Connell, 2003). It is synthesized from ornithine (an amino acid) through multiple enzymatic steps, which are outlined in Figure 3 (Sengbusch, Peter v. 2003).

Figure 3. The biosynthesis of nicotine in tobacco plants begins with the amino acid ornithine, which is then converted, through multiple enzymatic steps, to nicotine.

Nicotinic acetylcholine receptors normally bind the neurotransmitter acetylcholine. Structurally, the receptors are made up of multiple subunits (a₁-a₁₀ , b₁-b₄), which come together to form an ion channel. When the ligand (like acetylcholine) binds the receptor, the channel opens and ions flow through causing the transmission of neuronal singals. Ligand specificity is determined by the composition of the channel. Channels can be heteromeric, containing different subunits, or be homomeric, containing multiple copies of one type of subunit (West, K. A., et al. 2003).

Figure 5. Examples of nAchRs.

Carcinogenic components of cigarette smoke

Cigarettes contain over 4000 different chemicals, at least 43 of which are known to be carcinogenic. Others are known cause birth defects. For a comprehensive list of these, please visit the Arizona Smoker’s Helpline and click on Cigarette Smoke.

NNK, a carcinogenic metabolite of Nicotine

Figure 6. Nicotine is metabolized to NNK through multiple steps. NNK is a very toxic carcinogen and is known to cause lung cancer.

An important carcinogenic metabolite of nicotine is 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Once nicotine is introduced into the body it is metabolized to NNK by enzymes in the body.

Nicotine is first converted to 2'-hydroxynicotine, then to 4-(methylamino)-1-(3-pyridyl)-1-butanone, and finally to NNK (Hecht, S. A. et al. 2000).

NNK is known to cause lung cancer no matter how nicotine is introduced into the body (West, K. A., et al. 2003).

Smoking has been linked heavily to many diseases, especially emphysema and lung cancer.

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What is Cancer?

Cancer is the name given to cells that have broken the boundaries of normal cell proliferation and location. In order for a cell to become cancerous, it must first be able to divide without regulation, and then move to a new location and continue to survive. Cancers develop slowly and require multiple genetic mutations in key genes responsible for controlling cell division and cell behavior.

Preventing Cancer

The body does have mechanisms to prevent cancer formation. DNA damage, caused by environmental carcinogens or mistakes in DNA replication can be repaired if they are caught in time. The cell cycle has checkpoints to ensure that all the processes necessary for the cell to divide occur properly and if something goes wrong, then the cell cycle arrests until the mistake is corrected. Specific proteins ensure that these checkpoints are in place and normally the cell can divide if it passes each checkpoint. If a cell cannot correct its mistakes, it activates a cell suicide mechanism, known as apoptosis. This is done to ensure that cells with DNA damage or other regulatory damage do not continue to grow and disrupt the cells around them. If any of these checkpoints, repair mechanisms, or apoptotic pathways are disrupted, the opportunity for cancer development greatly increases.

Figure 7. In this example, a cell of the epithelium obtains a mutation that causes it to divide without control; it then obtains a second mutation that causes it to divide and grow even more; finally a third mutation causes the cell to break its normal location boundaries and invade the surrounding tissues. If the cells invade the blood stream, they can travel to new parts of the body and begin growing there. This is now known as metastatic cancer.