The S1P, formed from sphingosine by SphK1, can be irreversibly degraded by S1P lyase (SPL) leading to the formation of a long-chain aldehyde and phosphoethanolamine. With regard to cell growth and cancer, a potential role of SPL in regulating cell fate and stress responses has been investigated in several model systems. For example, mutations in the Dictyostelium sglA gene, which encodes SPL, confer resistance to the anticancer drug cisplatin.
On the contrary, enforced expression of SPL enhances the sensitivity to the drug. SPL has also been shown to sensitize mammalian cells to various stress stimuli including DNA damage. The overexpression of SPL sensitizes malignant and non-transformed human cells to platinum-based chemotherapies and etoposide.
Conversely, knockdown of endogenous SPL expression by siRNA strategy results in diminished apoptosis in etoposide-treated cells. Importantly, SPL expression is downregulated during intestinal tumorigenesis in the Min mouse model, as well as in human colon cancer specimen. Moreover, alterations of SPL expression in several types of cancers have been demonstrated by cDNA microarrays. Hence, in contrast to the oncogenic role of SphK1, which generates S1P, these findings suggest that SPL by degrading S1P might act as a tumor suppressor.
To date, besides the finding that SPL is one of the numerous genes downregulated by the miR-125b, an androgen regulated miRNA 20, nothing is known about the role of SPL in prostate cancer. In vitro and in vivo manipulation of SPL activity are currently carried out to investigate its role in tumor progression as well as its response to docetaxel-based chemotherapy, radiotherapy and androgen privation in prostate cancer.