EMBARGOED by Proceedings of the National Academy of Sciences for 5 p.m. EDT, Monday, June 30, 2003

Method Used by COX-2 Enzymes in Development of Colon Cancer
Described by UCSD Medical Researchers

The precise molecular interactions that allow cyclooxygenase-2 (COX-2) enzymes to promote the development of colon cancer have been described for the first time by researchers at the University of California, San Diego (UCSD) School of Medicine.

In lab studies with human and rat cells, the investigators defined the multiple steps initiated by COX-2, including a prominent role for a molecule called cyclic adenosine monophosphate (cAMP) and proteins called Inhibitors of Apoptosis (IAPs). The result of these molecular interactions is suppression of the body's natural cell-killing process, resulting in uncontrolled cell growth and eventual colon cancer.

Published online the week of June 30, 2003 in the journal Proceedings of the National Academy of Sciences, the findings also explain how aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce the incidence of colon cancer by inhibiting COX-2 and allowing the body to resume its normal process of killing unwanted or harmful cells.

Although colon cancer was studied, the findings have potential implications for understanding non-intestinal cancers where COX-2 or related enzymes play a role similar to that in colorectal cancer, said the paper's senior author, Paul Insel, M.D., UCSD professor of pharmacology and medicine. These may include certain lung cancers, prostate cancer, head and neck squamous cell carcinomas, and some breast cancers.

In addition, by pinpointing each step in the molecular chain-of-events initiated by COX-2 enzymes, the study offers potential new targets for drug therapies that have fewer side effects than NSAIDs, which can cause problems such as stomach irritation.

Schematic overview of the major apoptosis pathways and their inhibitors. Apoptosis through the death receptor (“extrinsic”) pathway involves activation of the initiator caspase 8, a process which can be inhibited by FLIP. The mitochondria-mediated “intrinsic” pathway is activated by different stimuli and conditions (only some of which are shown), which leads to release of pro-apoptotic factors from mitochondria, including cytochrome c, and activation of caspase 9. This step can be inhibited by the anti-apoptotic members of the Bcl-2 family of apoptosis regulators. Active caspases 8 and 9 convert the pro-form of caspase 3 to an active form, which initiates apoptotic cell death through activation of the other executioner caspases 6 and 7 and degradation of multiple death substrates. Active caspase 3 can be inhibited by IAP family members. For clarity, not all known steps and interactions within and between different pathways are depicted.

Prior to these findings, researchers have known that one of the earliest molecular events in 80 percent of colon cancers is over expression of COX-2 enzymes. Although clinical studies have provided unequivocal evidence that long-term use of NSAIDs inhibited COX-2 enzymes and was associated with a 40 to 50 percent reduction in the incidence of colon cancers, the precise mechanism of action was not understood.

Lars Eckmann, M.D., UCSD assistant professor of medicine and a co-author of the paper, explained that researchers have known that normal cell death is inhibited in colon cancer, resulting in overgrowth of harmful cells. The new findings determine how this happens.

In the intestines and other tissue, cells are generated and then die by a normal process called apoptosis. In the normal intestine, cells originate deep within the tissue, then migrate to the surface, where they undergo apoptotic cell death. In colon cancer, however, the cells "hang around too long and forget how to die," Eckmann explained.

A complicated process, apoptosis is a result of balanced molecular actions taking place at two different starting points. An "extrinsic" pathway, also called the death receptor pathway, activates one set of molecules. A second, "intrinsic" pathway is mediated by small cellular organelles called mitochondria. Like a letter "Y," the two pathways meet and join as they cause chemical reactions down a final pathway, resulting in a specific cell's death.

The research team headed by Insel and Eckmann used sophisticated laboratory analysis to determine that apoptosis was interrupted by IAP, an Inhibitor of Apoptosis Protein, at the point where the two pathways merge.

Specifically, the inhibition of apoptosis begins when COX-2 enzymes lead to the formation of prostaglandins, hormone-like chemical messengers that normally act as cell regulators for smooth muscle relaxation and regulation of blood pressure. On the road to colon cancer, however, prostaglandins trigger an increased production of cAMP, which is known to stimulate a variety of cellular activities. In this case, cAMP is able to block apoptosis on both pathways by activating IAPs.

The study was funded by grants from the National Institutes of Health, the Rebecca and John Moores UCSD Cancer Center, and the Stein Institute for Research on Aging. In addition to Insel and Eckmann, authors of the paper were first author Hiroshi Nishihara, M.D., Ph.D., UCSD Department of Pharmacology, and Shinae Kizaka-Kondoh, M.D., Ph.D., Department of Molecular Oncology, Kyoto University Graduate School of Medicine, Japan.

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