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Sphingosine-1-phosphate lyase potentiatesapoptosis via p53-and p38-dependentpathways and isdown-regulated incolon cancer Babak OskouianPrathap SooriyakumaranAlexander D. Borowsky2006 год

Sphingosine-1-phosphate lyase potentiates apoptosis via p53- and p38-dependent pathways and is down-regulated in colon cancer
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Аннотация: 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.
Год издания: 2006
Авторы: Babak Oskouian, Prathap Sooriyakumaran, Alexander D. Borowsky, Angelina Crans, Lisa Dillard‐Telm, Yuen Yee Tam, Padmavathi Bandhuvula, Julie D. Saba
Издательство: National Academy of Sciences
Источник: Proceedings of the National Academy of Sciences
Ключевые слова: Sphingolipid Metabolism and Signaling, Endoplasmic Reticulum Stress and Disease, Protein Kinase Regulation and GTPase Signaling
Другие ссылки: Proceedings of the National Academy of Sciences (HTML)
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