The marine sphingolipid-derived compound ES 285 triggers an atypical cell death pathway.
The isolation of new molecules from marine sources opens the door to their possible therapeutic use against tumors and other pathological conditions. Indeed, we recently defined the cytotoxicity of ES 285, obtained from the clam Mactromeris polynima, and its affects on the cells microfilament but not the microtubule network. Considering the analogy between ES 285 and sphingosine-related lipids, we wondered whether ES 285 might affect the activity of PKC at the intracellular level. While we anticipated that ES 285 might inhibit PKC, it turns out that in contrast it serves to activate PKC at the cellular level. Indeed, like other sphingosine-related lipids, ES 285 induces the phosphorylation of MARCKS. Additionally, we further examined the cytotoxicity of ES 285 to elucidate the molecular mechanisms through which this compound triggers apoptosis. When the influence of ES 285 on "cell death markers" was assessed, it became clear that ES285 activates caspase 3 and 12, and that it modified the phosphorylation of p53. In contrast, ES 285 does not affect other pathways widely implicated in regulating cell survival/apoptosis, such as JNK, Erks or Akt. Thus, these data suggest that ES 285-triggers an atypical cell death program when compared to other sphingosine-dependent apoptosis pathways.
Salcedo
M
M
Centro de Biología Molecular Severo Ochoa, Facultad de Ciencias, Universidad Autónoma de Madrid, 28049, Madrid, Spain.
Cuevas
C
C
Alonso
J L
JL
Otero
G
G
Faircloth
G
G
Fernandez-Sousa
J M
JM
Avila
J
J
Wandosell
F
F
D000473:Alkanes / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D061945:Caspase Inhibitors; D016923:Cell Death / Q000187:drug effects; D002457:Cell Extracts; D045304:Cytochromes c / Q000378:metabolism; D004075:Diglycerides / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D007928:Lethal Dose 50; D008055:Lipids / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D008928:Mitochondria / Q000187:drug effects; D041681:NIH 3T3 Cells; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D021381:Protein Transport / Q000187:drug effects; D013107:Sphingolipids / Q000737:chemistry / Q000494:pharmacology*; D013347:Subcellular Fractions / Q000187:drug effects; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D000473:Alkanes; D061945:Caspase Inhibitors; D002457:Cell Extracts; D004075:Diglycerides; D004791:Enzyme Inhibitors; D008055:Lipids; D013107:Sphingolipids; D016159:Tumor Suppressor Protein p53; C038237:1-oleoyl-2-acetylglycerol; D045304:Cytochromes c; D011493:Protein Kinase C; C408363:spisulosine