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Method Used By Enzymes In Development Of Colon Cancer Described By UCSD Researchers

Date:
July 4, 2003
Source:
University Of California - San Diego
Summary:
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.
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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.

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.


Story Source:

The above post is reprinted from materials provided by University Of California - San Diego. Note: Materials may be edited for content and length.


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University Of California - San Diego. "Method Used By Enzymes In Development Of Colon Cancer Described By UCSD Researchers." ScienceDaily. ScienceDaily, 4 July 2003. <www.sciencedaily.com/releases/2003/07/030701223231.htm>.
University Of California - San Diego. (2003, July 4). Method Used By Enzymes In Development Of Colon Cancer Described By UCSD Researchers. ScienceDaily. Retrieved August 28, 2015 from www.sciencedaily.com/releases/2003/07/030701223231.htm
University Of California - San Diego. "Method Used By Enzymes In Development Of Colon Cancer Described By UCSD Researchers." ScienceDaily. www.sciencedaily.com/releases/2003/07/030701223231.htm (accessed August 28, 2015).

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