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 #
2P01CA077839-11A1
Application #
8248355
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (O1))
Project Start
2011-12-01
Project End
2012-11-30
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
11
Fiscal Year
2012
Total Cost
$329,553
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Hsu, Alice H; Lum, Michelle A; Shim, Kang-Sup et al. (2018) Crosstalk between PKC? and PI3K/AKT Signaling Is Tumor Suppressive in the Endometrium. Cell Rep 24:655-669
Liang, Xiaohuan; Daikoku, Takiko; Terakawa, Jumpei et al. (2018) The uterine epithelial loss of Pten is inefficient to induce endometrial cancer with intact stromal Pten. PLoS Genet 14:e1007630
Wang, Dingzhi; DuBois, Raymond N (2018) Role of prostanoids in gastrointestinal cancer. J Clin Invest 128:2732-2742
Yuan, Jia; Deng, Wenbo; Cha, Jeeyeon et al. (2018) Tridimensional visualization reveals direct communication between the embryo and glands critical for implantation. Nat Commun 9:603
Mendelson, Karen; Pandey, Suveg; Hisano, Yu et al. (2017) The ceramide synthase 2b gene mediates genomic sensing and regulation of sphingosine levels during zebrafish embryogenesis. Elife 6:
Yanagida, Keisuke; Hla, Timothy (2017) Vascular and Immunobiology of the Circulatory Sphingosine 1-Phosphate Gradient. Annu Rev Physiol 79:67-91
Cha, Jeeyeon; Dey, Sudhansu K (2017) Hunting for Fox(A2): Dual roles in female fertility. Proc Natl Acad Sci U S A 114:1226-1228
Wang, Dingzhi; Sun, Haiyan; Wei, Jie et al. (2017) CXCL1 Is Critical for Premetastatic Niche Formation and Metastasis in Colorectal Cancer. Cancer Res 77:3655-3665
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:
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

Showing the most recent 10 out of 336 publications