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Dietary sphingolipids, colitis and colitis-associated colon cancer

A connection between inflammation and cancer has been recognized for over a hundred years, exemplified by Virchow’s observation that cancer behaves like a wound that does not heal (1, 2) . This connection is particularly evident in colon carcinogenesis, because patients with inflammatory bowel disease (IBD) have a higher incidence of colon cancer than the general population (3). Key inflammatory pathways are constitutively activated in many colorectal cancers, and inflammatory infiltrates and elevated cytokines are often present (4) . As developing nations westernize, both IBD and colon cancer incidence rise in association with the adoption of unhealthy diets (5). Together, these findings implicate a link between diet, inflammation and colon cancer. It has been suggested that genetic mutations are the “match that lights the fire” of cancer, whereas inflammation is the “fuel that feeds the flame” (2). However, there is increasing evidence that inflammation contributes to the earliest stages of carcinogenesis, namely in the process of cell transformation, where the cell acquires many aspects of the cancer phenotype (6) .

Bioactive sphingolipids play fundamental roles in carcinogenesis via their ability to regulate programmed cell death pathways, stress responses, angiogenesis, innate and adaptive immunity, and inflammation (7). The impact of sphingolipid metabolism is particularly germane in colon cancer, as gut epithelial cells are exposed to sphingolipid metabolites generated by the breakdown of dietary sphingolipids (8). Enzymes in the brush border generate sphingosine from higher-order mammalian sphingolipids. Sphingosine enters epithelial cells, where it is phosphorylated by sphingosine kinases, generating S1P. The S1P degradative enzyme S1P lyase (SPL) is highly expressed in enterocytes lining the gut mucosa, where it rapidly catabolizes S1P, thereby maintaining low levels of S1P relative to sphingosine in healthy gut tissues. During malignant transformation and colon cancer progression, the major sphingosine kinase, SphK1 is overexpressed (9-11) . In contrast, SPL is downregulated in colon adenomas and colon cancer, leading to accumulation of S1P (12, 13).

Not all sphingolipids are the same. In fact, sphingolipids derived from soy and other plant and non-mammalian sources are structurally different than mammalian sphingolipids. These structural differences result in biologically different effects on the gut mucosa. Whereas S1P promotes inflammation and carcinogenesis, plant/soy sphingolipids cannot be converted into S1P, are anti-inflammatory, and reduce the activity of several cancer signaling pathways including those involving AKT and WNT.

We recently explored the impact of intestinal SPL downregulation on colon carcinogenesis by generating and characterizing a gut-specific SPL knockout mouse. Our findings demonstrate that SPL plays a critical role in intestinal tumorigenesis by regulating extracellular levels of S1P formed from mammalian sphingosine, thereby affecting the induction of STAT3-activated miRNAs that contribute to the process of cell transformation. In contrast, we show that plant-type sphingolipids called sphingadienes (SDs) cannot be metabolized to S1P and instead enhance the metabolism of S1P by upregulating SPL. Our data suggest that dietary sphingolipids may enhance or inhibit colon carcinogenesis, depending on their ability to be metabolized to S1P. Our findings provide a mechanistic link between diet, inflammation and cancer and provide evidence supporting the further investigation of SDs as colon cancer chemopreventive agents.


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  2. Balkwill, F., and Mantovani, A. (2001) Inflammation and cancer: back to Virchow? Lancet 357, 539-545
  3. Beaugerie, L., Svrcek, M., Seksik, P., Bouvier, A. M., Simon, T., Allez, M., Brixi, H., Gornet, J. M., Altwegg, R., Beau, P., Duclos, B., Bourreille, A., Faivre, J., Peyrin-Biroulet, L., Flejou, J. F., and Carrat, F. (2013) Risk of colorectal high-grade dysplasia and cancer in a prospective observational cohort of patients with inflammatory bowel disease. Gastroenterology 145, 166-175 e168
  4. Terzic, J., Grivennikov, S., Karin, E., and Karin, M. (2010) Inflammation and colon cancer. Gastroenterology 138, 2101-2114 e2105
  5. McCormack, V. A., and Boffetta, P. (2011) Today's lifestyles, tomorrow's cancers: trends in lifestyle risk factors for cancer in low- and middle-income countries. Ann. Oncol. 22, 2349-2357
  6. Iliopoulos, D., Jaeger, S. A., Hirsch, H. A., Bulyk, M. L., and Struhl, K. (2010) STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Mol. Cell 39, 493-506
  7. Maceyka, M., Harikumar, K. B., Milstien, S., and Spiegel, S. (2012) Sphingosine-1-phosphate signaling and its role in disease. Trends Cell Biol. 22, 50-60
  8. Duan, R. D., and Nilsson, A. (2000) Sphingolipid hydrolyzing enzymes in the gastrointestinal tract. Methods Enzymol. 311, 276-286
  9. Kawamori, T., Kaneshiro, T., Okumura, M., Maalouf, S., Uflacker, A., Bielawski, J., Hannun, Y. A., and Obeid, L. M. (2009) Role for sphingosine kinase 1 in colon carcinogenesis. FASEB J. 23, 405-414
  10. Snider, A. J., Orr Gandy, K. A., and Obeid, L. M. (2010) Sphingosine kinase: Role in regulation of bioactive sphingolipid mediators in inflammation. Biochimie 92, 707-715
  11. Xia, P., Gamble, J. R., Wang, L., Pitson, S. M., Moretti, P. A., Wattenberg, B. W., D'Andrea, R. J., and Vadas, M. A. (2000) An oncogenic role of sphingosine kinase. Curr. Biol. 10, 1527-1530
  12. Oskouian, B., Sooriyakumaran, P., Borowsky, A., Crans, A., Dillard-Telm, L., Tam, Y., Bandhuvula, P., and Saba, J. (2006) Sphingosine-1-phosphate lyase potentiates apoptosis via p53- and p38-dependent pathways and is downregulated in colon cancer. Proc. Natl. Acad. Sci. U. S. A. 103, 17384-17389
  13. Kohno, M., Momoi, M., Oo, M., Paik, J., Lee, Y., Venkataraman, K., Ai, Y., Ristimaki, A., Fyrst, H., Sano, H., Rosenberg, D., Saba, J., Proia, R., and Hla, T. (2006) Intracellular role for sphingosine kinase 1 in intestinal adenoma cell proliferation. Mol. Cell. Biol. 26, 7211-7223

Revised: July 10, 2018 10:23 AM



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