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Mechanisms of smoking-related lung and pancreatic adenocarcinoma development

Key Points

  • Adenocarcinomas of the lung and pancreas are among the most common and most deadly cancers. They share two risk factors — smoking and high-fat diet — with cardiovascular disease.

  • The arachidonic acid (AA) cascade is important in cardiovascular disease, and the overexpression of the gene that encodes cyclooxygenase-2 (COX2) in pulmonary and pancreatic adenocarcinoma indicates that the AA-cascade is also involved in the development of these cancers.

  • A nicotine-derived nitrosamine, nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), causes adenocarcinomas of the lung and pancreas in laboratory animals, and is thought to be largely responsible for the development of these cancers in smokers.

  • NNK has genotoxic effects on cells, such as the formation of DNA adducts and mutations in the RAS gene. These effects of NNK probably cause the development of cancers that express such gene mutations (30% of pulmonary and 50–90% of pancreatic adenocarcinomas).

  • NNK also has epigenetic effects on pulmonary and pancreatic cells by functioning as an agonist for β-adrenergic receptors. This reaction activates various signal-transduction pathways, and causes the release of AA followed by the formation of mitogenic AA metabolites. These β-adrenergic-receptor-mediated events activate transcription and cell proliferation, and are thought to cause pulmonary and pancreatic adenocarcinomas that do not express RAS mutations, as well as synergizing with the cancer-causing effects of mutated RAS.

  • β-Blockers, inhibitors of AA-metabolizing enzymes and a low-fat diet are already widely used for the treatment and prevention of cardiovascular disease. The data compiled in this review indicate that they will also be effective for the treatment and prevention of pulmonary and pancreatic adenocarcinomas.

  • Overexpression of COX2 in adenocarcinomas of the colon, prostate and breast, as well as recent reports that β-adrenergic signalling regulates growth of these cancers, indicate that adenocarcinomas at these organ sites might also be treated or prevented with β-blockers. They might also be treated with pharmacological or dietary inhibitors of the AA cascade.

Abstract

Adenocarcinoma of the lungs and pancreas are among the most common and most deadly smoking-associated cancers. Cigarette smoke contains various toxic chemicals, including a carcinogenic nitrosamine, nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). One of the most well-known features of NNK is the ability of its metabolites to bind to DNA and induce activating point mutations in the RAS gene. But NNK is also a β-adrenergic-receptor agonist that stimulates arachidonic acid release, leading to the formation of mitogenic metabolites that stimulate DNA synthesis and cell proliferation. NNK therefore contributes to tobacco-induced carcinogenesis by several mechanisms.

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Figure 1: Structures of nicotine, NNK and β-adrenergic-receptor agonists.
Figure 2: Potential mitogenic signal transduction pathways activated by binding of NNK to β-adrenergic receptors expressed in pulmonary and pancreatic adenocarcinomas.
Figure 3: Indirect growth stimulation of pulmonary and pancreatic adenocarcinomas in smokers by nicotine.

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DATABASES

Cancer.gov

breast cancer

colon cancer

lung cancer

pancreatic cancer

prostate cancer

LocusLink

ATF-1

B-RAF

COX2

Cox2

CREB

CREM

cyclin D1

cytochrome P450

EGF

EGFR

ERK1

ERK2

interleukin-3

K-ras

K-RAS

5-LOX

12-LOX

15-LOX

MAPK

MEKs

MYC

NF-κB

phospholipase-A2

PKA

RAF-1

RAP1

RAS

RSKs

c-SRC

STAT3

Medscape DrugInfo

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atenolol

celecoxib

docetaxel

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OMIM

asthma

FURTHER INFORMATION

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Glossary

PANCREATIC DUCTAL/DUCTULAR EPITHELIUM

The pancreas contains a network of ducts that branch into smaller ductules, the inner lining of which are called ductal and ductular epithelium, respectively.

DNA ADDUCT

DNA bound to a chemical compound.

NITROSATION

Nitrosation is a chemical reaction that adds two nitrogen atoms and one oxygen atom — which comprise the 'nitroso group' — to another chemical.

INTRATRACHEAL INSTILLATION

'Trachea' is the Latin word for windpipe. When agents such as chemicals or drugs are given by a tube inserted into the mouth through the larynx into the windpipe, this is called an intratracheal instillation. This form of drug administration is used to make sure that the drug goes directly into the lungs.

N3 POLYUNSATURATED FATTY ACIDS

Fatty acids consist of a chain of carbon and hydrogen atoms with the acidic carboxyl group 'COOH' at the end. The term 'polyunsaturated' means that the carbon chain includes double bonds. The term 'N3' means that the first double bond starts at the third carbon atom on the side of the molecule that is opposite to the carboxyl group.

CATECHOLAMINES

Adrenaline and noradrenaline (also known S-adrenaline) are produced by cells in the adrenal gland. They are called catecholamines because their chemical structure is characterized by the presence of a catechol ring.

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Schuller, H. Mechanisms of smoking-related lung and pancreatic adenocarcinoma development. Nat Rev Cancer 2, 455–463 (2002). https://doi.org/10.1038/nrc824

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