A new investigation by the Children’s Hospital and Research Center Oakland has linked mammalian sphingolipids to inflammation and cancer. A sphingolipid metabolite called sphingosine-1-phosphate (S1P) found in both mammalian food products and generated by normal human cells can contribute to inflammation of the colon, inflammatory bowel disease (IBD) and inflammation-associated colon cancer, whereas soy and plant-type sphingolipids called sphingadienes may protect against these conditions.
The connection between IBD and colon cancer is associated with a predominantly western style diet in industrialized nations. Bioactive sphingolipids play fundamental roles in creating cancer as they regulate programmed cell death pathways, stress responses, immunity, and inflammation. The impact of the sphingolipid metabolism is relevant in colon cancer, as gut epithelial cells are exposed to sphingolipid metabolites generated by the breakdown of dietary sphingolipids. S1P, the final breakdown product of mammalian sphingolipids, is a pro-inflammatory signaling lipid that promotes cell growth and the production of cancer. During malignant transformation and colon cancer progression, genetic changes occur in the gut tissues, including an increase in the enzyme that generates S1P and a decrease in S1P lyase (SPL), the enzyme that catalyzes S1P degradation. These changes lead to accumulation of S1P in the gut mucosa.
A mouse, lacking SPL in the gut tissue, was used to simulate the effect of S1P accumulation on inflammation and carcinogenesis. In contrast to control mice, the mutated mice exhibited more inflammation and a higher incidence of tumors. Using a combination of mouse and cell culture experiments, the scientists identified a cascade of steps downstream of S1P that lead eventually to the silencing of two tumor suppressing proteins whose functions are to protect against the formation of cancer.
Soy or plant-type sphingolipids called sphingadienes, on the other hand, cannot be metabolized to S1P. Mice treated with sphingadiene had reduced inflammation, signs of IBD, and incidence of tumors.
The study findings revealed a link between diet, inflammation and cancer. Sphingadienes act as colon cancer preventative agents in patients at risk, such as children and adults with IBD.
Emilie Degagné, Ashok Pandurangan, Padmavathi Bandhuvula, Ashok Kumar, Abeer Eltanawy, Meng Zhang, Yuko Yoshinaga, Mikhail Nefedov, Pieter J. de Jong, Loren G. Fong, Stephen G. Young, Robert Bittman, Yasmin Ahmedi, Julie D. Saba. Sphingosine-1-phosphate lyase downregulation promotes colon carcinogenesis through STAT3-activated microRNAs. Journal of Clinical Investigation, 2014; DOI: 10.1172/JCI74188