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Eicosanoid Biochemistry Group

Lipid Involvement in Cancer

Thomas E. Eling
Thomas E. Eling, Ph.D.
Principal Investigator - Scientist Emeritus
Tel (919) 541-3911
Fax (919) 541-0146
eling@niehs.nih.gov
P.O. Box 12233
Mail Drop E4-09
Research Triangle Park, North Carolina 27709
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Research Summary

The Eicosanoid Biochemistry Group focuses on how nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the development of tumors, the role of receptors in biological responses of prostaglandins in cancer and how the over-expression of cyclooxygenase 2 (COX-2) alters cells.

 

Prostaglandin H synthases, also called cyclooxygenases (COX-1/2), and lipoxygenases (LOX) metabolize unsaturated fatty acids to prostaglandins, leukotrienes, and related metabolites. Prostaglandins and leukotrienes bind to specific receptors to produce an extremely diverse array of biological activities linked to many important human diseases such as cancer, cardiovascular disease, and inflammatory diseases. A large number of important drugs are based on either inhibiting the formation of metabolites or blocking the receptors, and, as a result, the activity of the lipid metabolites. These enzymes and receptors play an important role in the development of human colon, prostate, breast, and other cancers. COX inhibitors reduce human mortality due to colorectal and other cancers by 40-60 percent.

 

The figure illustrates the response elements in the NAG-1 promoter controlling the increase in expression by drugs and chemicals.

The Eicosanoid Biochemistry Group wants to understand how these lipids, enzymes responsible for their formation, and their receptors participate in the development of cancer. In studying this problem, it has found that COX inhibitors alter gene expression and increase the expression of a novel member of the TGF-β family the group has named NAG-1. In addition to NSAIDs, a number of drugs and environmental chemicals increase the expression of NAG-1. The group has also characterized the promoter element that controls expression of NAG-1 (see figure). Studies with stably transfected cells suggest that NAG-1 regulates apoptosis and acts to suppress tumor growth.

 

The Eicosanoid Biochemistry Group has developed a NAG-1 transgenic mouse, which appears to be normal, but it is leaner and has a reduced body fat compared to its littermates. NAG-1 transgenic mice are resistant to chemically- and genetically-induced intestinal cancer. These studies also indicate a suppression of lung and prostate cancer. In addition, NAG-1 appears to have anti-inflammatory activity. NAG-1 transgenic mice have reduced inflammatory responses to lipopolysaccaride (LPS) and lower intestinal inflammation. The results suggest that the NFκB/TLR4 pathway is suppressed either directly or indirectly in the transgenic mouse and provides a link between tumor suppression and inflammation.

 

Several clinical studies are in progress to investigate the NAG-1 link to prostate cancer and inflammatory bowel disease. Other studies on the epigenetic regulation of NAG-1 confirmed that as a result of hyper-methylation of the critical promoter elements, NAG-1 expression is silenced in many tumors. The investigation into the tumor suppressor and anti-inflammatory activities of NAG-1 has developed into the major focus of the group.

 

Evidence clearly links the development of human cancer to the environment. Not only does exposure to chemicals cause tumor formation, other factors can also play a role in the progression and development of cancer. In contrast, the environment can also act to prevent or retard tumor growth. For example, the lipid composition of diet can act to increase or lower cancer risk and appears to be linked to the metabolism of unsaturated fatty acids. Many dietary chemicals influence lipid metabolism and alter the expression of NAG-1, and thus, alter cancer risk.

 

How the environment influences cancer by altering lipid metabolism and expression of the tumor suppressor NAG-1 is poorly understood. Obesity is a growing problem and a leading cause of illness, including cancer. Because NAG-1 mice are leaner and resistant to cancer, they may serve as a model system to studying the link between obesity and cancer. Recently, the Eicosanoid Biochemistry Group placed both wild-type and NAG-1 transgenic mice on a high fat diet. The wild-type mice had a large increase in body weight and abdominal fat while the NAG-1 transgenic mice did not gain weight or abdominal fat. The group will explore this problem further, including whether a correlation exists between abdominal fat content and the development of intestinal tumors.

 

Major areas of research:

  • The involvement of Cox and Lox enzymes in the development and progression of cancer
  • The involvement of Cox inhibitors in preventing the development of tumors

 

Current projects:

  • Using the Cox-2-Cre-Lox-P mouse to determine how Cox-2 participates in tumor development and progression
  • Crossing Tramp mice with NAG-1-Tg mice to examine if the expression of NAG-1 alters prostate cancer progression and development

 

Thomas E. Eling, Ph.D., leads the Eicosanoid Biochemistry Group within the Laboratory of Molecular Carcinogenesis. He earned his Ph.D. in 1968 from the University of Alabama. He has published more than 270 peer-reviewed articles in leading biomedical journals, as well as several book chapters.

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