Arachidonic acid (AA) metabolism and downstream eicosanoid signaling pathways are well-established targets for colon cancer chemopreventive agents. AA is generated in tumor cells by the actions of phospholipases. One phospholipase of particular interest is cytoplasmic phospholipase A2 (cPLA2). This enzyme contributes to the production of cancer-promoting prostaglandins (PGs) via the Cox-2-catalyzed conversion of AA. Additionally, cPLA2 regulation of intracellular AA levels affects apoptotic signaling, as AA not consumed by Cox-2 controls sphingomyelin conversion to ceramide, a key death effector. Using BALB/c mice that are deficient in cPLA2, we obtained evidence that the growth inhibitory role of cPLA2 in colon via apoptosis regulation may predominate over its role as a tumor promoter through prostaglandin synthesis. We propose a series of in vivo studies in mice and in vitro studies in colon cancer cells to evaluate the role of cPLA2 in the pathogenesis of colorectal cancer (CRC).
Aim 1 will test the hypothesis that cPLA2 suppresses colon carcinogenesis through its actions on AA metabolism and the sphingomyelinase (Smase) - ceramide apoptotic pathway. We will evaluate the cPLA2 effect in AOM- and ApcMin-initiated tumors. These studies will provide a comprehensive view of how cPLA2 status impacts intestinal tumorigenesis.
Aim 2 will explore mechanisms by which cPLA2 controls tumor cell growth. We will harvest tumor cells from cPLA2-null mice and test their growth in vitro and in an orthotopic model using syngeneic mice. Mechanistic studies will be performed using a conditional Tet-off cPLA2 expression system to evaluate a panel of apoptotic effectors.
Aim 3 will test the influence of cPLA2 on chemoprevention by the Cox inhibitor, sulindac. Efficacy will be evaluated in mice with normal or reduced levels of cPLA2. Since Cox inhibitors are only effective on a subset of lesions, we will use a novel chromendoscopic imaging approach to predict and track the effects of chemoprevention on the biological fate of individual AOM-induced adenomas with different cPLA2 genetic backgrounds. Genetic signatures of responsive and non-responsive adenomas will be developed that may be used to target chemoprevention strategies to responsive individuals at the greatest risk for CRC. Predicting drug response through molecular profiling of adenomas will become an important consideration in cancer prevention. Our goal would be to improve targeting of individuals most likely to respond to chemopreventive agents that impact the AA metabolic pathway. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA114635-01A2
Application #
7213860
Study Section
Special Emphasis Panel (ZRG1-ONC-T (02))
Program Officer
Yang, Shen K
Project Start
2006-09-28
Project End
2011-07-31
Budget Start
2006-09-28
Budget End
2007-07-31
Support Year
1
Fiscal Year
2006
Total Cost
$318,622
Indirect Cost
Name
University of Connecticut
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Montrose, David C; Nakanishi, Masako; Murphy, Robert C et al. (2015) The role of PGE2 in intestinal inflammation and tumorigenesis. Prostaglandins Other Lipid Mediat 116-117:26-36
Nakanishi, Masako; Rosenberg, Daniel W (2013) Multifaceted roles of PGE2 in inflammation and cancer. Semin Immunopathol 35:123-37
Nakanishi, Masako; Menoret, Antoine; Tanaka, Takuji et al. (2011) Selective PGE(2) suppression inhibits colon carcinogenesis and modifies local mucosal immunity. Cancer Prev Res (Phila) 4:1198-208
Montrose, David C; Horelik, Nicole A; Madigan, James P et al. (2011) Anti-inflammatory effects of freeze-dried black raspberry powder in ulcerative colitis. Carcinogenesis 32:343-50
Greenspan, Emily J; Madigan, James P; Boardman, Lisa A et al. (2011) Ibuprofen inhibits activation of nuclear {beta}-catenin in human colon adenomas and induces the phosphorylation of GSK-3{beta}. Cancer Prev Res (Phila) 4:161-71
Greenspan, Emily J; Nichols, Frank C; Rosenberg, Daniel W (2010) Molecular alterations associated with sulindac-resistant colon tumors in ApcMin/+ mice. Cancer Prev Res (Phila) 3:1187-97
Montrose, David C; Kadaveru, Krishna; Ilsley, Jillian N M et al. (2010) cPLA2 is protective against COX inhibitor-induced intestinal damage. Toxicol Sci 117:122-32
Nakanishi, Masako; Gokhale, Vijay; Meuillet, Emmanuelle J et al. (2010) mPGES-1 as a target for cancer suppression: A comprehensive invited review ""Phospholipase A2 and lipid mediators"". Biochimie 92:660-4
Nakanishi, Masako; Montrose, David C; Clark, Patsy et al. (2008) Genetic deletion of mPGES-1 suppresses intestinal tumorigenesis. Cancer Res 68:3251-9
Mounier, C M; Wendum, D; Greenspan, E et al. (2008) Distinct expression pattern of the full set of secreted phospholipases A2 in human colorectal adenocarcinomas: sPLA2-III as a biomarker candidate. Br J Cancer 98:587-95

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