The sphingolipid degradation product trans-2-hexadecenal induces cytoskeletal reorganization and apoptosis in a JNK-dependent manner |
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Authors: | Kumar Ashok Byun Hoe-Sup Bittman Robert Saba Julie D |
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Institution: | a Center for Cancer Research, Children''s Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609, USAb Queens College of the City University of New York, Department of Chemistry and Biochemistry, Flushing, NY 11367, USA |
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Abstract: | The bioactive signaling molecule d-erythro-sphingosine-1-phosphate (S1P) is irreversibly degraded by the enzyme S1P lyase (SPL). The reaction of SPL with C18-S1P generates ethanolamine phosphate and a long-chain fatty aldehyde, trans-2-hexadecenal. Modulation of SPL expression in cells and organisms produces significant phenotypes, most of which have been attributed to corresponding changes in S1P-dependent signaling. However, the physiological functions of SPL products are not well understood. In the present study, we explored the biological activities of trans-2-hexadecenal in human and murine cells. We demonstrate that trans-2-hexadecenal causes cytoskeletal reorganization leading to cell rounding, detachment and eventual cell death by apoptosis in multiple cell types, including HEK293T, NIH3T3 and HeLa cells. Trans-2-hexadecenal stimulated a signaling pathway involving MLK3 and the respective phosphorylation of MKK4/7 and JNK, whereas ERK, AKT and p38 were unaffected. Trans-2-hexadecenal-induced apoptosis was accompanied by activation of downstream targets of JNK including c-Jun phosphorylation, cytochrome c release, Bax activation, Bid cleavage and increased translocation of Bim into mitochondria. The antioxidant N-acetylcysteine prevented JNK activation by trans-2-hexadecenal. Further, inhibition of JNK abrogated the cytoskeletal changes and apoptosis caused by trans-2-hexadecenal, whereas Rac1 and RhoA were not involved. In conclusion, our studies provide a new paradigm of sphingolipid signaling by demonstrating for the first time that S1P metabolism generates a bioactive product that induces cellular effects through oxidant stress-dependent MAP kinase cell signaling. |
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Keywords: | DAPI 4&prime 6-diamidino-2-phenylindole dihydrochloride hydrate FALDH fatty aldehyde dehydrogenase HDL high density lipoprotein HEK293T human embryonic kidney cell line 293T JNK c-Jun N-terminal kinase MKK4/7 MAP kinase kinase 4/7 MLK3 mixed lineage kinase 3 NAC N-acetyl cysteine PARP poly (ADP-ribose) polymerase ROS reactive oxygen species S1P sphingosine-1-phosphate SPC sphingosylphosphorylcholine SPL sphingosine-1-phosphate lyase |
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