The long-term goal of this research is to help develop improved chemopreventive interventions for colorectal cancer based on molecular targeting of crucial events in colorectal tumorigenesis. Inflammation contributes to colon carcinogenesis. Prostaglandin E2 (PGE2), a proinflammatory product of arachidonic acid, activates peroxisome proliferator-activated receptor-delta (PPAR-d) and promotes colonic tumorigenesis. Arachidonic acid is frequently formed from linoleic acid especially in cancer cells. Direct metabolism of linoleic acid by 15- lipoxygenase-1 (15-LOX-1) to 13-hydroxyoctadecadienoic acid (13-S-HODE) has antitumorigenic and antiinflammatory effects. 15-LOX-1 and 13-S-HODE are downregulated during human colonic tumorigenesis. 15-LOX-1 re-expression in colon cancer cells downregulates PPAR-d via 13-S-HODE and inhibits colon cancer cell growth in vitro and in vivo. The hypothesis to be tested is that restoring 15-LOX-1 expression, and thus 13- S-HODE production, will prevent colitis-induced promotion of colonic tumorigenesis, reduce the availability of linoleic acid for conversion to arachidonic acid and PGE2, and thus suppress PPAR-d.
Aim 1 : To determine the effects of 15-LOX-1 on the conversion of dietary linoleic acid in colonic epithelial cells into 13-S-HODE vs. PGE2 during the development of chronic colitis. LC/MS/MS will be used to examine the effects of targeted transgenic 15-LOX-1 expression in mouse colonic epithelial mucosa on the conversion of deuterated linoleic acid (supplemented to colonic crypt cells) into 13-S-HODE and PGE2 in mice treated with dextran sodium sulfate (DSS) to induce colitis.
Aim 2 : To determine whether 15-LOX-1 suppresses chronic colitis. The effects of 15-LOX-1 expression on clinical and histologic colitis scores will be examined in mice with colitis induced by DSS or IL-10 knockout.
Aim 3 : To determine whether 15-LOX-1 prevents colitis-induced promotion of colonic tumorigenesis. The effects of transgenic15-LOX-1 expression on colon tumor incidence and multiplicity will be examined in mice treated with AOM-DSS and IL-10 knockout mice. The effects of 15-LOX-1 expression on 13- S-HODE and PGE2 levels in mice with and without dietary PGE2 supplementation, will clarify the contribution of reduced PGE2 vs. increased 13-S-HODE to the 15-LOX-1 antiinflammatory and antitumorigenic effects of 15-LOX-1 in Aims 2 and 3.
Aim 4 : To determine whether PPAR-d overexpression contributes to colitis-induced promotion of colonic tumorigenesis and whether 15-LOX-1 inhibits tumorigenesis via PPAR-d downregulation. The effects of targeted villin-PPAR-d overexpression on colitis-induced promotion of colonic tumorigenesis will be studied in mice treated with AOM-DSS. Bigenic PPAR-d and 15-LOX-1 transgenic mice will be used to study the contribution of PPAR-d downregulation to the effects of 15-LOX-1 on colitis-induced promotion of colonic tumorigenesis. The project-generated information will provide important insights into the molecular mechanisms involved in colonic tumorigenesis and thus help develop new interventions for the chemoprevention of colon cancer.
Decreased production of the enzyme 15-lipoxygenase-1 (15-LOX-1) is associated with colon cancer development;however, the molecular mechanisms involved need to be clarified. The proposed project aims to improve understanding of the molecular mechanisms by which loss of 15-LOX-1 contributes to both colitis and colon cancer. This improved understanding is expected to facilitate the identification of molecular targets for new strategies for colon cancer prevention.
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