Therapeutic Potential for Sphingolipids in Inflammatory Bowel Disease and Colorectal Cancer

Abstract

Inflammatory bowel disease (IBD), characterized by chronic inflammation in the intestinal tract, increases the risk for the development of colorectal cancer (CRC). Sphingolipids, which have been implicated in IBD and CRC, are a class of bioactive lipids that regulate cell signaling, differentiation, apoptosis, inflammation, and survival. The balance between ceramide (Cer), the central sphingolipid involved in apoptosis and differentiation, and sphingosine-1-phosphate (S1P), a potent signaling molecule involved in proliferation and inflammation, is vital for the maintenance of normal cellular function. Altered sphingolipid metabolism has been implicated in IBD and CRC, with many studies highlighting the importance of S1P in inflammatory signaling and pro-survival pathways. A myriad of sphingolipid analogues, inhibitors, and modulators have been developed to target the sphingolipid metabolic pathway. In this review, the efficacy and therapeutic potential for modulation of sphingolipid metabolism in IBD and CRC will be discussed.

Keywords: ceramide; colitis-associated cancer; colorectal cancer; inflammation; inflammatory bowel disease; sphingolipids; sphingosine-1-phosphate.

Figure 1

Sphingolipid metabolism and potential interventions. Ceramide is at the center of sphingolipid metabolism, and can be generated via the de novo, hydrolytic, or salvage pathways. Ceramide plays several roles in arresting cellular activity, and can be utilized to generate complex membrane sphingolipids, or deacylated to generate sphingosine and eventually the potent signaling molecule S1P. With the exception of S1PR, various enzymes (in red), which have been implicated in inflammation, can be targeted with inhibitors. S1PRs, the receptors for S1P, can be inhibited with specific inhibitors and/or downregulated by S1PR modulators. Lastly, ceramide analogues increase ceramide pools to drive its biological effects.

Figure 2

Altered sphingolipid metabolism in IBD and CRC promote inflammation. Early events in IBD and cancer trigger the over-expression of CerS, increasing the generation of ceramide species. Elevations in Cer can then drive apoptosis, differentiation, and cell cycle arrest. However, Cer also influences expression of CDases and SK1. Distinct pools of Cer can then be deacylated to generate sphingosine and phosphorylated into S1P. S1P signaling is mediated via autocrine to paracrine signaling via S1PRs, which are also highly expressed during inflammation, increasing S1P signaling to promote proinflammatory cytokine secretion, cell survival, and proliferation.