Sphingosine-1-phosphate lyase potentiates apoptosis via p53- and p38-dependent pathways and is down-regulated in colon cancer

Babak Oskouian, Prathap Soonyakumaran, Alexander D Borowsky, Angelina Crans, Lisa Dillard-Telm, Yuen Yee Tam, Padmavathi Bandhuvula, Julie D. Saba

Research output: Contribution to journalArticle

139 Citations (Scopus)

Abstract

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 down-regulated 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.

Original languageEnglish (US)
Pages (from-to)17384-17389
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number46
DOIs
StatePublished - Nov 14 2006

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Lyases
Colonic Neoplasms
Apoptosis
Ceramides
DNA Damage
Carcinogenesis
sphingosine 1-phosphate lyase (aldolase)
Caspase 2
Sphingolipids
HEK293 Cells
p38 Mitogen-Activated Protein Kinases
Epigenomics
Real-Time Polymerase Chain Reaction
Down-Regulation
Cell Proliferation
sphingosine 1-phosphate

Keywords

  • Etoposide
  • Intestinal tumorigenesis
  • Min mouse
  • Sphingolipid

ASJC Scopus subject areas

  • Genetics
  • General

Cite this

Sphingosine-1-phosphate lyase potentiates apoptosis via p53- and p38-dependent pathways and is down-regulated in colon cancer. / Oskouian, Babak; Soonyakumaran, Prathap; Borowsky, Alexander D; Crans, Angelina; Dillard-Telm, Lisa; Tam, Yuen Yee; Bandhuvula, Padmavathi; Saba, Julie D.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 103, No. 46, 14.11.2006, p. 17384-17389.

Research output: Contribution to journalArticle

Oskouian, Babak ; Soonyakumaran, Prathap ; Borowsky, Alexander D ; Crans, Angelina ; Dillard-Telm, Lisa ; Tam, Yuen Yee ; Bandhuvula, Padmavathi ; Saba, Julie D. / Sphingosine-1-phosphate lyase potentiates apoptosis via p53- and p38-dependent pathways and is down-regulated in colon cancer. In: Proceedings of the National Academy of Sciences of the United States of America. 2006 ; Vol. 103, No. 46. pp. 17384-17389.
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T1 - Sphingosine-1-phosphate lyase potentiates apoptosis via p53- and p38-dependent pathways and is down-regulated in colon cancer

AU - Oskouian, Babak

AU - Soonyakumaran, Prathap

AU - Borowsky, Alexander D

AU - Crans, Angelina

AU - Dillard-Telm, Lisa

AU - Tam, Yuen Yee

AU - Bandhuvula, Padmavathi

AU - Saba, Julie D.

PY - 2006/11/14

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N2 - 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 down-regulated 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.

AB - 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 down-regulated 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.

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