S1P Lyase in colon cancer
Principal Investigator: Julie Saba
Affiliation: Children's Hospital Oakland Research Institute
Abstract: DESCRIPTION (provided by applicant): Dietary sphingolipids such as ceramide and sphingosine promote apoptosis and protect against intestinal tumorigenesis. However, these sphingolipids can be converted within intestinal cells to sphingosine-1- phosphate (S1P), a potent mitogen and angiogenic factor. Thus, a delicate balance exists between these sphingolipid metabolites in gut epithelial cells, alterations of which may influence intestinal tumorigenesis. S1P is irreversibly degraded by the enzyme S1P lyase (SPL), which promotes apoptosis and is required for maximal apoptotic responses. SPL is highly expressed in gut epithelium, where it maintains low S1P levels and promotes normal cell turnover. However, we have found that SPL is downregulated in early Min mouse polyps and in human colon cancer. We hypothesize that SPL downregulation is an early event in intestinal tumorigenesis, representing a critical genetic change that leads to a biochemical switch favoring S1P accumulation in the intestinal mucosa, thereby activating mitogenic and angiogenic signals that contribute to tumor progression. To test this possibility, we have proposed four interrelated specific aims: 1. To characterize the changes in S1P metabolism that accompany intestinal tumorigenesis. We hypothesize that genetic and/or epigenetic changes leading to S1P accumulation are common and early events in intestinal tumorigenesis. Sphingolipid levels and the activity, expression and localization of enzymes involved in S1P metabolism will be compared in human intestinal polyps, CRC, Min mouse polyps of different stages and corresponding uninvolved tissues;2. To establish whether SPL expression affects the growth characteristics of immortalized and malignant colonic epithelial cells in vitro. SPL expression will be modulated in malignant and nonmalignant colon epithelial cell lines using siRNA, adenoviral and stable expression systems. Effects on proliferation, apoptosis, migration and tumorigenicity and mechanism of SPL action will be determined. 3. To establish whether SPL downregulation increases intestinal tumorigenicity and alters the response to dietary sphingolipids. Available SPL knockout mouse models crossed into the Min mouse background will be used to explore the hypothesis that reduced SPL expression and increased S1P levels in mouse intestinal tissues will enhance the rate, incidence, growth, vascularity and invasive characteristics of intestinal polyposis and limit or reverse the chemopreventive effect of dietary sphingolipids;4. To determine whether SPL downregulation is reversible early in intestinal tumorigenesis. We will investigate the hypothesis that SPL downregulation is the result of epigenetic changes involving DNA methylation at the SPL genomic locus. The proposed research plan should establish whether SPL downregulation is an early and reversible event that contributes to intestinal tumorigenesis. In accomplishing the proposed studies, we will move closer to our long term goal of employing chemopreventive measures to restore the delicate sphingolipid metabolic balance early in the process of tumorigenesis.Project Narrative Colon cancer is the second most common cancer of men and women and the third leading cause of cancer mortality. It is estimated that $8.4 billion per year is spent caring for patients with this disease in the US. Identifying the molecular and environmental determinants of disease incidence and progression is a critical goal that may help to reveal novel biomarkers for earlier detection and therapeutic intervention to help the 50% or more of patients suffering from advanced or refractory disease. If our central hypothesis is correct, the status of S1P metabolic genes may become informative biomarkers in predicting outcome and the response to therapeutic and dietary regimens. Our Research Plan should establish the validity of this hypothesis and provide information necessary for achieving our ultimate goal, which is to identify and validate novel therapeutic approaches that bypass or reverse the sphingolipid metabolic switch and restore normal S1P metabolism in premalignant and/or malignant cells.
Funding Period: 2007-09-21 - 2012-07-31
more information: NIH RePORT
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Department of Dermatology, School of Medicine, University of California, San Francisco, Veterans Affairs Medical Center, San Francisco, California, USA
Mol Cell Biol 33:752-62. 2013....
- Immunohistochemical analysis of sphingosine phosphate lyase expression during murine developmentSusan Newbigging
Centre for Modeling Human Disease, Samuel Lunenfeld Research Institute, Mount Sinai Hospital, The Toronto Centre for Phenogenomics, University of Toronto, Toronto, Ontario, Canada
Gene Expr Patterns 13:21-9. 2013..Our findings are consistent with the SPL expression pattern of the adult mouse and with congenital abnormalities observed in SPL mutant mice...
- Sphingosine-1-phosphate lyase expression in embryonic and adult murine tissuesAlexander D Borowsky
Center for Comparative Medicine, University of California at Davis, Davis, CA 95616, USA
J Lipid Res 53:1920-31. 2012..This unique expression pattern suggests SPL has many undiscovered physiological functions apart from its role in immunity...
- The sphingolipid degradation product trans-2-hexadecenal forms adducts with DNAPramod Upadhyaya
Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA
Biochem Biophys Res Commun 424:18-21. 2012..Thus, our findings suggest that trans-2-hexadecenal produced endogenously by sphingosine 1-phosphate lyase can react directly with DNA forming aldehyde-derived DNA adducts with potentially mutagenic consequences...
- Chemopreventive sphingadienes downregulate Wnt signaling via a PP2A/Akt/GSK3β pathway in colon cancerAshok Kumar
Center for Cancer Research, Children s Hospital Oakland Research Institute, Oakland, CA 94609, USA
Carcinogenesis 33:1726-35. 2012..Our cumulative findings indicate that SDs inhibit Wnt signaling through a protein phosphatase 2A/Akt/GSK3β-dependent mechanism that may contribute to their chemopreventive effects in intestinal tumorigenesis...
- Sphingolipid signaling and hematopoietic malignancies: to the rheostat and beyondKenneth C Loh
Children s Hospital Oakland Research Institute, Center for Cancer Research, CA 94609, USA
Anticancer Agents Med Chem 11:782-93. 2011..Here, we summarize recent insights regarding the sphingolipid metabolic pathway and its role in hematopoietic malignancies...
- The sphingolipid degradation product trans-2-hexadecenal induces cytoskeletal reorganization and apoptosis in a JNK-dependent mannerAshok Kumar
Center for Cancer Research, Children s Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA 94609, USA
Cell Signal 23:1144-52. 2011....
- Cancer treatment strategies targeting sphingolipid metabolismBabak Oskouian
Children s Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, California, 94609 1673, USA
Adv Exp Med Biol 688:185-205. 2010..Pharmacological tools for modulating sphingolipid pathways are being developed and represent novel therapeutic strategies for the treatment of cancer...
- An update on sphingosine-1-phosphate and other sphingolipid mediatorsHenrik Fyrst
Center for Cancer Research, Children s Hospital Oakland Research Institute, Oakland, California, USA
Nat Chem Biol 6:489-97. 2010....
- S1P metabolism in cancer and other pathological conditionsWeng In Leong
Children s Hospital Oakland Research Institute, 5700 Martin Luther King, Jr Way, Oakland, CA 94609, USA
Biochimie 92:716-23. 2010....
- Sphingosine 1-phosphate lyase deficiency disrupts lipid homeostasis in liverMeryem Bektas
Genetics of Development and Disease Branch, NHLBI, National Institutes of Health, Bethesda, Maryland 20892, USA
J Biol Chem 285:10880-9. 2010..The disturbance of lipid homeostasis by altered sphingolipid levels may be relevant to metabolic diseases...
- Natural sphingadienes inhibit Akt-dependent signaling and prevent intestinal tumorigenesisHenrik Fyrst
Children s Hospital Oakland Research Institute, Oakland, California 94609 1673, USA
Cancer Res 69:9457-64. 2009..Thus, sphingadienes represent a new class of therapeutic and/or chemopreventive agents that blocks Akt signaling in neoplastic and preneoplastic cells...
- Lyase to live by: sphingosine phosphate lyase as a therapeutic targetAshok Kumar
Children s Hospital Oakland Research Institute CHORI, Oakland, CA 94609 1673, USA
Expert Opin Ther Targets 13:1013-25. 2009..SPL has been directly implicated in various physiological and pathological processes, including cell stress responses, cancer, immunity, hematopoietic function, muscle homeostasis, inflammation and development...
- Sphingosine-1-phosphate lyase in development and disease: sphingolipid metabolism takes flightHenrik Fyrst
Children s Hospital Oakland Research Institute, 5700 Martin Luther King Jr Way, Oakland, CA 94609, USA
Biochim Biophys Acta 1781:448-58. 2008..This review provides an overview of our current understanding of SPL structure and function, mechanisms involved in SPL regulation and the role of SPL in development and disease...