Sphingosine Kinase as a Target to Treat Gastrointestinal Cancers

Gastrointestinal cancer is a malignant condition of the gastrointestinal tract including the esophagus, stomach, small and large intestine, rectum, and anus. About 4.8 million new cases of gastrointestinal cancer were recorded in 2020. Current treatment options of gastrointestinal cancers have failed to treat the disease condition and newer approaches are under investigation. One such approach includes targeting the sphingosine kinase, a critical enzyme in sphingolipid metabolism. Known as structural molecules of the cellular membrane, sphingolipids, and their metabolism have emerged as important components of cellular functions like cell proliferation, cell survival, and cell apoptosis. Over the last few years, most of the enzymes involved in the metabolism of sphingolipids have been extensively studied, which has enlightened the primary roles of these metabolic enzymes in the sphingolipid metabolic pathway. Ceramide and sphingosine are synthesized mainly by oxidative stress, and chemotherapy/radiation which mediates apoptosis, and cell cycle arrest, while sphingosine-1-phosphate (S1P) converted from ceramide, has proliferation and antiapoptotic properties. Findings regarding the nature of ceramide and/or S1P lead to evaluating the potential target enzymes, which are involved in the metabolism of ceramide and S1P. Sphingosine kinase HK1 (SPHK1) and sphingosine kinase HK2 (SPHK2) are diacylglycerol kinase family which converts ceramide into S1P. The overexpression of SPHK1 and SPHK2 has been documented in various cancers. Many in vitro and in vivo studies have been carried out to evaluate the role of sphingosine kinase in cancer. Based on the findings, few pharmacological interventions are under clinical study. This chapter includes sphingolipid metabolism and its essential enzymes, the role of sphingolipids and metabolic enzymes in cancer, potential enzyme targets for the treatment of cancer, and molecules under investigation.