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Eicosanoid Biochemistry Group

Lipid Involvement in Cancer

Not Pictured
Thomas E. Eling, Ph.D.
Principal Investigator

Tel (919) 541-3911
Fax (919) 541-0146
P.O. Box 12233
Mail Drop E4-09
Research Triangle Park, North Carolina 27709
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Research Summary

The metabolism of the cis-unsaturated fatty acids, arachidonic acid and linoleic acid by prostaglandin H synthases (Cox-1/-2) and lipoxygenases (Lox) to diverse array of biologically active lipids is a critical component in the development of cancer. Cox-2 expression is high in most tumors while 15-Lox’s expression is altered in colorectal and prostate cancer. The expression of Cox-2 results in elevated levels of prostaglandins in the developing tumor. Recent studies have provided some in sight into the molecular mechanisms for how these lipids metabolites increase tumor progression. The prostaglandins bind to specific receptors and initiate signal pathways modulating critical pathways linked to cancer development. However, this is clearly not fully understood and further studies are required. In addition, the use of Cox inhibitors (NSAIDs) lowers cancer mortality and reduces the development and progression colorectal cancer and other cancers. Cox inhibitors act to prevent cancer by inhibiting prostaglandin formation but clearly other mechanisms, independent of Cox inhibition are also involved.

The Eicosanoid Biochemistry Group addresses two questions:

  1. How do the Cox and Lox enzymes participate in the development and progression of cancer?
  2. How do the Cox inhibitors inhibit or prevent the development of tumors?

15-Lipoxygenase-1 expression is altered in human colorectal tumors and is induced by histone deacetylase inhibitors in human colorectal cells with a corresponding decrease in cell growth and induction of apoptosis. Based data obtained from xenograph mouse models, 15-Lox-1 acts as a tumor suppressor. Recently, the group found 15-Lox-1 to increase the activation of p53 by increasing the phosphorylation at serine 15. As a result the expression of the many down stream targets genes of p53 are increased. Currently, group members are investigating the interaction between the kinases that phosphorylated p53 and 15-Lox-1 to determine the mechanisms responsible.

To study how Cox-2 participates in tumor development and progression, the group has developed a Cox-2-Cre-Lox-P mouse that can be breed to produce tissue specific Cox-2 expression. Initially we generated a mouse with ubiquitous Cox-2 expression that proved to be fatal to the offspring. The mice had several malformations and appeared to die from patent ductus and/or pulmonary edema but further investigations must be completed.

Since the last review investigation studies concerned with the how Cox inhibitors prevent cancer has been the major focus of the laboratory. The group’s hypothesis is that these drugs attenuate cancer progression by not only inhibit prostaglandin formation but also by altering gene expression. Physiology concentrations of Cox inhibitors alter the expression of a number of genes linked to cancer including a previously uncharacterized member of the TGFβ superfamily that the Eicosanoid Biochemistry Group has named NAG-1 (NSAID Activated Gene). The over-expression of NAG-1 in cancer cells results in growth arrest and increase in apoptosis, suggesting that NAG-1 has anti-tumorigenic activity. The group has developed a transgenic mouse by the Cre-Lox-P technique and initially made mice ubiquitously expressing human NAG-1. The transgenic mice appear to be normal but are 15-20% smaller. The Nag-1-Tg mice are resistant to the development of intestinal tumors following treatment with azoxymethane or by introduction of a mutant APC gene into the mice. Current studies are underway with the Tramp mice, a model for human prostate cancer, and have crossed the Tramp mice with NAG-1-Tg mice to examine if the expression of NAG-1 alters prostate cancer progression and development.

The expression of NAG-1 can be increased in vivo and in vitro by treatment with drugs and chemicals documented to prevent tumor formation and development. We have devoted a major effort to studying the regulation of NAG-1 expression. The regulation of NAG-1 is complex and many of chemicals act through p53 or Egr-1 related pathways. In addition, an increase in NAG-1 is observed on inhibition of the AKT/GSK-3β pathway, suggesting NAG-1 alters cell survival. Thus, NAG-1 expression is regulated by several tumor suppressors and the expressed protein inhibits tumor progression and development. Cox Inhibitors like sulfide sulfide that have excellent anti-tumor activity strongly increase NAG-1 expression. These drugs regulate NAG-1 expression by modulation of the Egr-1/SP1 transcription factors reported to regulate the expression of other genes. Sulindac sulindac at early times after treatment increases Egr-1 expression resulting in higher expression of NAG-1 and thrombospondin-1 (TSP-1), a protein with anti-angiogenic and anti-invasion activities. At later times, sulindac sulfide increase SP-1 expression and phosphorylation that subsequently suppresses the expression of the prostaglandin receptor, EP4, reported to be important on cancer progression. Thus this drug increases the expression of anti-cancer proteins and suppresses the expression of pro-tumorigenic proteins. The group proposes that Cox inhibitors like sulindac sulfide act to impair tumor progression by reducing prostaglandin levels and by altering the expression of proteins that regulated apoptosis, angiogenesis and tumor invasion.

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 250 peer-reviewed articles in leading biomedical journals as well as several book chapters.

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Last Reviewed: September 11, 2007