New understanding of sphingosine kinases called SphK1 and SphK2

Virginia Commonwealth University Massey Cancer Center researchers have found that two enzymes that catalyze the same reaction and produce the same product have opposite effects on cell growth and death.

These findings may help researchers develop cancer therapies that target one enzyme, while leaving the other alone.

In the November issue of the Journal of Biological Chemistry, Sarah Spiegel, Ph.D., professor and chair in the Department of Biochemistry at the VCU School of Medicine and co-leader of the Massey Cancer Center Cell Signaling program, and researchers in her lab showed that sphingosine kinases called SphK1 and SphK2, a family of enzymes that forms the potent lipid mediator sphingosine-1-phosphate (S1P), have opposing roles in the regulation of ceramide biosynthesis. S1P is a molecule that has been shown to promote tumor cell growth and inhibit cell death.

They found that the different effects of SphK1 and SphK2 may arise because they act at different locations within the cell. In addition, the data suggest that SphK2 can sensitize cancer cells to chemotherapy, and therefore may be a potential target for cancer therapy.

"In this study, we found that it is not what the reaction produces, but where it occurs that determines the ultimate effects," said lead author Michael Maceyka, Ph.D., a Massey Cancer Center trainee in the Department of Biochemistry at VCU.

"Understanding that SphK1 and SphK2 have opposite effects on cell growth may be helpful in creating more effective chemotherapeutic agents designed to target a specific sphingosine kinase without acting on the other."

Maceyka and the Spiegel group showed that SphK1 decreased levels of the sphingolipid known as ceramide, while SphK2 increased these levels. According to Maceyka many chemotherapy agents increase the level of ceramide in a cell, which is necessary in order for the agent to kill tumor cells. Sphingolipids are essential components of cell membranes for all animal and plant cells.

"These results highlight the importance of designing inhibitors of exquisite selectivity. Our findings highlight some critical information - just because two enzymes catalyze the same reaction does not mean that targeting one will have the same effect as targeting the other," he said.

S1P is an important signaling molecule that cells use to communicate with one another and to trigger various effects within the cell. S1P has also been implicated in many processes contributing to cancer progression, including growth, survival and angiogenesis, the process by which tumor cells recruit new blood vessels that both feed the tumor with nutrients and provide a conduit for the tumor cells to spread throughout the body.