Sphingolipid mediators, are involved in complex cell signaling pathways that regulate cell growth, apoptosis and differentiation. Dietary sphingomyelin is avidly metabolized in the intestinal tract into polar metabolites such as sphingosine and sphingosine 1-phosphate (S1P). Our laboratory defined the first G protein-coupled receptor for SIP and characterized its receptor-dependent actions. Merrill and colleagues have shown that dietary sphingomyelin is chemopreventive in carcinogen-induced and tumor-suppressor gene deleted (ApcMin/+) models of intestinal tumorigenesis. In addition, increased intake of sphingolipid-rlch diets (such as soy), which raises intracellular sphingosine levels is associated with reduced Incidence of intestinal cancer. These data suggest that sphingolipid mediators are potent modulators of intestinal tumorigenesis. This proposal is based on the hypothesis that sphingosine kinase is a key regulatory enzyme that facilitates intestinal tumorigenesis by suppressing intracellular levels of tumor suppressor lipid sphingosine and enhancing pro-tumorigenic lipid mediator SIP. We propose to further define molecular mechanisms and test the biological significance in mouse models of intestinal cancer. Thus, the specific aims are: 1. To further define the role of sphingosine kinase enzymes in intestinal tumorigenesis. 2. To define the molecular mechanisms involved in the intracellular signaling of sphingosine, 3. We will test the hypothesis that increased intracellular sphingosine and reduced autocrine signaling of 81P brought about by gene deletion of Sphk enzymes is responsible for tumor suppressive action. Dietary sphingomyelin will be used to further Increase sphingosine levels in Sphk knockout mice and we will test whether this dietary manipulation further influences intestinal tumorigenesis in the ApcMin/-t- model. Since sphingolipid levels in the intestine can be altered by dietary means, this research promises to provide a novel means of cancer chemoprevention.

Public Health Relevance

Sphingolipid mediators regulate cell signaling events and modulate cell proliferation, apoptosis and angiogenesis. We propose that dietary sphingolipid intake, and metabolism in the intestinal tract, produces sphingolipid mediators that suppress intestinal cancer. This research will elucidate mechanisms and attempt to develop a novel way of intestinal cancer prevention.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA077839-13
Application #
8677710
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
13
Fiscal Year
2014
Total Cost
$348,644
Indirect Cost
$24,803
Name
Mayo Clinic, Arizona
Department
Type
DUNS #
153665211
City
Scottsdale
State
AZ
Country
United States
Zip Code
85259
Sun, Xiaofei; Park, Craig B; Deng, Wenbo et al. (2016) Uterine inactivation of muscle segment homeobox (Msx) genes alters epithelial cell junction proteins during embryo implantation. FASEB J 30:1425-35
Wang, Dingzhi; DuBois, Raymond N (2016) The Role of Prostaglandin E(2) in Tumor-Associated Immunosuppression. Trends Mol Med 22:1-3
Hiraoka, Takehiro; Hirota, Yasushi; Saito-Fujita, Tomoko et al. (2016) STAT3 accelerates uterine epithelial regeneration in a mouse model of decellularized uterine matrix transplantation. JCI Insight 1:
Yuan, Jia; Cha, Jeeyeon; Deng, Wenbo et al. (2016) Planar cell polarity signaling in the uterus directs appropriate positioning of the crypt for embryo implantation. Proc Natl Acad Sci U S A 113:E8079-E8088
Reddy, Vishruth K; Short, Sarah P; Barrett, Caitlyn W et al. (2016) BVES Regulates Intestinal Stem Cell Programs and Intestinal Crypt Viability after Radiation. Stem Cells 34:1626-36
Sones, Jenny L; Cha, Jeeyeon; Woods, Ashley K et al. (2016) Decidual Cox2 inhibition improves fetal and maternal outcomes in a preeclampsia-like mouse model. JCI Insight 1:
Etemadi, Nima; Chopin, Michael; Anderton, Holly et al. (2015) TRAF2 regulates TNF and NF-κB signalling to suppress apoptosis and skin inflammation independently of Sphingosine kinase 1. Elife 4:
Proia, Richard L; Hla, Timothy (2015) Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy. J Clin Invest 125:1379-87
Li, Mei-Hong; Swenson, Rolf; Harel, Miriam et al. (2015) Antitumor Activity of a Novel Sphingosine-1-Phosphate 2 Antagonist, AB1, in Neuroblastoma. J Pharmacol Exp Ther 354:261-8
Wang, Dingzhi; Fu, Lingchen; Sun, Haiyan et al. (2015) Prostaglandin E2 Promotes Colorectal Cancer Stem Cell Expansion and Metastasis in Mice. Gastroenterology 149:1884-1895.e4

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