Date of Award

2000

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

First Advisor

Daniel Hwang

Abstract

Dietary n-3 fatty acids and non-steroidal anti-inflammatory drugs (NSAIDs) were shown to have cancer preventive and tumor regressive effects. Fatty acids and NSAIDs are substrate and inhibitors, respectively, of cyclooxygenase-2 (COX-2), which is a key enzyme in the conversion of arachidonic acids to prostaglandins. Thus, the modulating effects of different types of dietary fatty acids and NSAIDs on the expression of COX-2 are studied here. Results show that both n-3 and n-6 polyunsaturated fatty acids (PUFAs) inhibit Lipopolysaccharide (LPS)-induced COX-2 expression and NF-kappaB activation in macrophages. Results from in vitro cell proliferation study indicate that growth of colon tumor cells is suppressed by n-3 PUFAs as compared with n-6 PUFAs regardless of whether COX-1 or COX-2 is expressed or not. These results suggest that signaling pathways through which PUFAs inhibit tumor cell growth and LPS-induced COX-2 expression may be different. Unlike the previous study in human colon carcinoma cells, NSAIDs, especially flufenamic acid and sulindac sulfide, upregulate the expression of COX-2 under both the presence and absence of COX-2 stimulators in a normal intestinal cell line, IEC-6 cells. The inhibitors of extracellular-signal-regulated protein kinase (ERK), and p38 MAP kinase inhibit the flufenamic acid-induced COX-2 expression, suggesting that flufenamic acid-induced COX-2 expression is at least partly mediated through activation of MAPKs in IEC-6 cells. TNFalpha-induced activation of NF-kappaB was suppressed by flufenamic acid or sulindac sulfide. However, these NSAIDs did not appear to affect TNFalpha-induced COX-2 expression in IEC-6 cells. This may be due to two opposing effects: one is induction of COX-2 by NSAIDs and the other is induction of TNFalpha-induced COX-2 expression by NSAIDs. The results from theses studies provide new insight for signaling pathways through which fatty acids and NSAIDs modulate COX-2 and other inflammatory marker gene products.

ISBN

9780599906259

Pages

113

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