Sphingosine-1-Phosphate Lyase Potentiates Apoptosis via p53- and p38-Dependent Pathways and Is Down-Regulated in Colon Cancer

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 103; no. 46; pp. 17384 - 17389
• Main Authors: Oskouian, Babak, Sooriyakumaran, Prathap, Borowsky, Alexander D., Crans, Angelina, Dillard-Telm, Lisa, Tam, Yuen Yee, Bandhuvula, Padmavathi, Saba, Julie D.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 14.11.2006; National Acad Sciences
• Subjects: Aldehyde-Lyases - deficiency; Aldehyde-Lyases - genetics; Aldehyde-Lyases - metabolism; Animals; Apoptosis; B lymphocytes; Biological Sciences; Carrier Proteins - metabolism; Catalysis; Cell Line; Cell lines; Cell Transformation, Neoplastic; Ceramides; Colonic Neoplasms - genetics; Colonic Neoplasms - metabolism; Colonic Neoplasms - pathology; Colorectal cancer; Death Domain Receptor Signaling Adaptor Proteins; Directional control; DNA - genetics; DNA damage; DNA Damage - genetics; Down-Regulation; Enzymes; Gene Expression Regulation, Neoplastic; HEK293 cells; Humans; Intestinal Polyps - genetics; Intestinal Polyps - metabolism; Intestinal Polyps - pathology; Metabolism; Mice; Mice, Inbred C57BL; Mice, Knockout; p38 Mitogen-Activated Protein Kinases - metabolism; Signal Transduction; Small interfering RNA; Sphingolipids; Studies; Tumor Suppressor Protein p53 - metabolism
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0600050103

Sphingolipid metabolites such as sphingosine-1-phosphate (S1P) and ceramide modulate apoptosis during development and in response to stress. In general, ceramide promotes apoptosis, whereas S1P stimulates cell proliferation and protects against apoptosis. S1P is irreversibly degraded by the enzyme S1P lyase (SPL). In this study, we show a crucial role for SPL in mediating cellular responses to stress. SPL expression in HEK293 cells potentiated apoptosis in response to stressful stimuli including DNA damage. This effect seemed to be independent of ceramide generation but required SPL enzymatic activity and the actions of p38 MAP kinase, p53, p53-inducible death domain protein (PIDD), and caspase-2 as shown by molecular and chemical inhibition of each of these targets. Further, SPL expression led to constitutive activation of p38. Endogenous SPL expression was induced by DNA damage in WT cells, whereas SPL knockdown diminished apoptotic responses. Importantly, SPL expression was significantly downregulated in human colon cancer tissues in comparison with normal adjacent tissues, as determined by quantitative real-time PCR (Q-PCR) and immunohistochemical analysis. Down-regulation of S1P phosphatases was also observed, suggesting that colon cancer cells manifest a block in S1P catabolism. In addition, SPL expression and activity were down-regulated in adenomatous lesions of the Min mouse model of intestinal tumorigenesis. Taken together, these results indicate that endogenous SPL may play a physiological role in stress-induced apoptosis and provide an example of altered SPL expression in a human tumor. Our findings suggest that genetic or epigenetic changes affecting intestinal S1P metabolism may correlate with and potentially contribute to carcinogenesis.