Dietary sphingolipids such as sphingosine and ceramide promote enterocyte turnover and have been shown to protect against intestinal tumorigenesis in mice. However, sphingosine taken up by enterocytes can be phosphorylated by the oncogenic enzyme SphK1, generating sphingosine-1-phosphate (S1P), a mitogenic lipid that inhibits apoptosis and promotes inflammation, transformation and carcinogenesis. Thus, dietary sphingolipids represent a double-edged sword in colon cancer. Elucidating their specific roles in carcinogenesis is a necessary first step to developing sphingolipid-based strategies to lower colon cancer risk. S1P is irreversibly degraded by the enzyme S1P lyase (SPL) which is highly expressed in enterocytes and other cellular compartments of the gut mucosa. We showed previously that SPL is downregulated in ApcMin/+ mouse adenomas and human colon cancers. We now show that SPL is also downregulated in tumors that develop in azoxymethane/dextran sodium sulfate (AOM/DSS)-treated mice. Thus, SPL downregulation is a common feature of intestinal neoplasia. We generated gut-specific SPL knockout mice (SPLGutKO) and demonstrated that loss of enterocyte SPL expression promotes tumorigenesis in ApcMin/+ mice and enhances colitis, enterocyte proliferation and tumor incidence in AOM/DSS-treated mice. Loss of SPL expression was associated with increased activation of STAT3, a critical regulator of inflammation, carcinogenesis and interactions between tumor cells and the tumor microenvironment or "niche". STAT3 acts as a transcription factor with many mRNA and microRNA targets. STAT3 has also been shown to regulate mitochondrial functions. Importantly, we found that inhibition of STAT3 prevented the ability of SPL disruption to promote tumorigenesis in AOM/DSS and xenograft model systems. In addition to these findings, we recently identified a family of soy-derived sphingolipids called sphingadienes (SDs) with chemopreventive action in mice. SDs promote enterocyte turnover, inhibit STAT3, WNT and AKT signaling pathways and, importantly, induce SPL expression in colon cancer cell lines. Our cumulative findings have led us to propose our central hypothesis, which states that: SPL downregulation promotes colon carcinogenesis through STAT3-dependent mechanisms that influence intestinal epithelial cells and other cellular compartments of the tumor niche. We further propose that SDs serve as an antidote to SPL downregulation by reversing it and its associated effects on colon inflammation and carcinogenesis. To test our hypothesis, we have devised four Specific Aims: 1) To clarify how S1P promotes cell transformation and tumorigenesis;2) To elucidate the role of SPL in modulating the tumor niche;3) To establish whether SPL downregulation promotes intestinal tumorigenesis induced by a pro-inflammatory diet;4) To test whether SDs can reverse SPL downregulation and its associated effects during intestinal tumorigenesis. In accomplishing these aims, we should achieve our two major goals: to elucidate the biology of SPL in colon cancer, and to develop chemopreventive strategies that work by reactivation of SPL.
Colon cancer is a major cause of cancer morbidity and mortality in the United States. Inflammation has been implicated as a contributing factor to the development of the disease. The studies we propose will clarify how the metabolism of dietary sphingolipids by cells of the gut can modulate intestinal inflammation and thereby influence the development of colon cancer. Understanding the influence of dietary sphingolipids on inflammation and cancer may help us to develop novel chemopreventive strategies to reduce the risk of developing colon cancer promoted by the Western diet, inflammatory bowel disease and other inflammatory conditions.
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|Degagné, Emilie; Saba, Julie D (2014) S1pping fire: Sphingosine-1-phosphate signaling as an emerging target in inflammatory bowel disease and colitis-associated cancer. Clin Exp Gastroenterol 7:205-14|
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|Newbigging, Susan; Zhang, Meng; Saba, Julie D (2013) Immunohistochemical analysis of sphingosine phosphate lyase expression during murine development. Gene Expr Patterns 13:21-9|
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|Oskouian, Babak; Saba, Julie D (2010) Cancer treatment strategies targeting sphingolipid metabolism. Adv Exp Med Biol 688:185-205|
|Fyrst, Henrik; Saba, Julie D (2010) An update on sphingosine-1-phosphate and other sphingolipid mediators. Nat Chem Biol 6:489-97|
|Serra, Montserrat; Saba, Julie D (2010) Sphingosine 1-phosphate lyase, a key regulator of sphingosine 1-phosphate signaling and function. Adv Enzyme Regul 50:349-62|
|Bektas, Meryem; Allende, Maria Laura; Lee, Bridgin G et al. (2010) Sphingosine 1-phosphate lyase deficiency disrupts lipid homeostasis in liver. J Biol Chem 285:10880-9|
|Leong, Weng In; Saba, Julie D (2010) S1P metabolism in cancer and other pathological conditions. Biochimie 92:716-23|
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