The importance of arachidonic acid (AA) and linoleic acid (LA) metabolism is supported by animal and human epidemiology studies that indicate that aspirin and other NSAIDs that inhibit Cox activity, reduce the incidence and mortality of colon cancer and reduce polyps in patients with familial polyposis. Experimental studies with rodents indicate that NSAIDs reduce both the size and number of colon tumors induced by carcinogens. Prostaglandins and other lipids play a major role in the development and progression of colon and other cancers but the mechanism is not clear. The expression of Cox and LOX and NSAID treatment is linked to altered apoptosis, cell growth, cell differentiation and angiogenesis. We are examining arachidonic acid and linoleic acid metabolism, and the expression of Cox-1 and -2, and lipoxygenases in human cell lines. In addition to Cox-2, the expression of 15-lipoxygenase is higher in colorectal and prostate tumors. Data support the hypothesis that histone acetylation regulates the expression of 15-lipoxygenase-1 in human intestinal epithelial cells. In prostate cells 15-LOX-1 has a pro-tumorigenic effect while in colorectal tissue the lipoxygenase has an anti-tumorigenic effect. These lipoxygenases and their metabolites alter growth factor signaling pathways and 15-HETE and 13-HODE, the metabolites of AA and LA have opposing biological responses. In addition, the laboratory is studying the expression and regulation of Cox-1 and Cox-2 in cells. One unexpected finding is the up-regulation of Cox-1 but not 15-LOX-1 by HDAC inhibitors in brain cells. Our plans are to continue to investigate the regulation of 15-LOX and Cox-1 &-2 and to focus on how these enzyme contribute to the development of cancers.

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES050144-08
Application #
6681967
Study Section
(LMC)
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2002
Total Cost
Indirect Cost
Name
U.S. National Inst of Environ Hlth Scis
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Kambe, Atsushi; Iguchi, Genzo; Moon, Yuseok et al. (2008) Regulation of EP4 expression via the Sp-1 transcription factor: inhibition of expression by anti-cancer agents. Biochim Biophys Acta 1783:1211-9
Lee, Craig R; Bottone Jr, Frank G; Krahn, Joseph M et al. (2007) Identification and functional characterization of polymorphisms in human cyclooxygenase-1 (PTGS1). Pharmacogenet Genomics 17:145-60
Lee, Seong-Ho; Yamaguchi, Kiyoshi; Kim, Jong-Sik et al. (2006) Conjugated linoleic acid stimulates an anti-tumorigenic protein NAG-1 in an isomer specific manner. Carcinogenesis 27:972-81
Okazaki, Ryuji; Moon, Yuseok; Norimura, Toshiyuki et al. (2006) Ionizing radiation enhances the expression of the nonsteroidal anti-inflammatory drug-activated gene (NAG1) by increasing the expression of TP53 in human colon cancer cells. Radiat Res 165:125-30
Kim, Jong-Sik; Baek, Seung Joon; Bottone Jr, Frank G et al. (2005) Overexpression of 15-lipoxygenase-1 induces growth arrest through phosphorylation of p53 in human colorectal cancer cells. Mol Cancer Res 3:511-7
Bottone Jr, Frank G; Martinez, Jeanelle M; Collins, Jennifer B et al. (2003) Gene modulation by the cyclooxygenase inhibitor, sulindac sulfide, in human colorectal carcinoma cells: possible link to apoptosis. J Biol Chem 278:25790-801
Baek, Seung Joon; Wilson, Leigh C; Hsi, Linda C et al. (2003) Troglitazone, a peroxisome proliferator-activated receptor gamma (PPAR gamma ) ligand, selectively induces the early growth response-1 gene independently of PPAR gamma. A novel mechanism for its anti-tumorigenic activity. J Biol Chem 278:5845-53
Nixon, J B; Kamitani, H; Baek, S J et al. (2003) Evaluation of eicosanoids and NSAIDs as PPARgamma ligands in colorectal carcinoma cells. Prostaglandins Leukot Essent Fatty Acids 68:323-30
Wilson, Leigh C; Baek, Seung Joon; Call, Allison et al. (2003) Nonsteroidal anti-inflammatory drug-activated gene (NAG-1) is induced by genistein through the expression of p53 in colorectal cancer cells. Int J Cancer 105:747-53
Amin, Ruhul; Kamitani, Hideki; Sultana, Habiba et al. (2003) Aspirin and indomethacin exhibit antiproliferative effects and induce apoptosis in T98G human glioblastoma cells. Neurol Res 25:370-6

Showing the most recent 10 out of 29 publications