The importance of arachidonic acid and linoleic acid metabolism is supported by animal and human epidemiology studies that indicate that aspirin and other NSAID drugs reduce the incidence and mortality of colon cancer. These drugs also induce regression of rectal polyps in patients with familial polyposis. Experimental studies with rodents indicate that NSAID reduce the both the size and number of colon tumors induced by carcinogens. Recent studies reported that PGHS-2 is significantly expressed in colon tumors compared to neighboring normal tissue. These data suggest that prostaglandins could play a major role in the development and progression of colon cancer. Our purpose to investigate the relationships between arachidonic acid metabolism and cell proliferation using a number of colon cell lines that are in several stages of differentiation and transformation. This project is in the early stages of development. We have obtained a number of colon cell lines that represent the various stages of genetic alterations that occur during the development of colon cancer. We are examining both arachidonic acid metabolism and the expression of PGHS-1 and-2 and cPLA2 in these cell lines. We will then measure the effect of NSAID drugs on growth factor induced (EGF,TGF) cell proliferation. Since some data suggest that prostaglandins can also alter apoptosis, we intend to determine if prostaglandins alter apoptosis in these cell lines. The effect of NSAID and prostaglandins could be due to either effects on cell proliferation or apoptosis. We observed in SW-480 cells that butyrate induced differentiation results in an increased expression of PGHS-1 and apoptosis. However, the addition of PGHS inhibitor did not alter the apoptosis in these cells. Further studies are planned using rat intestinal cell lines that high express PGHS-2 and are used as a model of colon cells. These studies will further define the potential use of NSAID as chemotherapeutic agents.
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