Increasing evidence supports a link between diet, inflammation, and colon cancer. In murine models, dietary supplementation with the sphingolipid sphingosine is protective against colon cancer; however, the phosphorylated form of sphingosine, sphingosine-1-phosphate (S1P), promotes tumorigenic transformation. S1P lyase (SPL), which degrades S1P, is highly expressed in healthy enterocytes but reduced in colon cancer, suggesting that sphingolipid metabolism influences colon cancer development. Emilie Degagné and colleagues at the Children’s Hospital Oakland Research Institute evaluated the contribution of SPL in colitis-associated cancer (CAC). Compared to control animals, mice lacking SPL in the intestinal epithelium were extremely susceptible to CAC, as evidenced by increased tumor formation and colon shortening in response to chemically induced colitis. S1P, STAT3 activation, STAT3-induced microRNAs, and inflammatory cytokines were all increased SPL-deficient mice, and STAT3 inhibition ameliorated CAC severity in these animals. In fibroblasts, loss of SPL enhanced extracellular transport of S1P, resulting in S1P receptor activation, induction of STAT3-dependent microRNAs, and silencing of tumor suppressor CYLD. Importantly, both S1P levels and STAT3 signaling were enhanced in biopsies from IBD patients. In mice, administration of sphingadienes, plant-type sphingolipids that cannot be metabolized to S1P, increased SPL production, thereby reducing S1P, STAT3 signaling, and tumorigenesis in response to chemically induced colitis. The results from this study reveal that dietary sphingolipids differentially influence intestinal carcinogenesis and suggest that sphingadienes have potential as protective agents against colon cancer. The accompanying image shows enhanced proliferation (Ki-67 staining) in colon sections from mice lacking SPL in the intestine (left) compared to control animals (right) in respsone to chemically induced colitis.
Growing evidence supports a link between inflammation and cancer; however, mediators of the transition between inflammation and carcinogenesis remain incompletely understood. Sphingosine-1-phosphate (S1P) lyase (SPL) irreversibly degrades the bioactive sphingolipid S1P and is highly expressed in enterocytes but downregulated in colon cancer. Here, we investigated the role of SPL in colitis-associated cancer (CAC). We generated mice with intestinal epithelium-specific
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