Cell-cell contacts trigger programmed necrosis and induce cyclooxygenase-2 expression.
Necrosis was induced by cell-cell contacts of human dermal fibroblasts in three-dimensional culture. Dramatic induction of cyclooxygenase-2 (COX-2) expression was found throughout these necrotizing cell clusters, whereas no increase in expression of apoptosis markers was seen. The cells were rapidly committed to necrosis, and the process could not be reversed by allowing them to spread and adhere on a solid substrate. Induction of COX-2 expression was accompanied by greatly enhanced production of the prostaglandins E(2), I(2), and F(2alpha). When applied exogenously on necrotizing clusters, these prostaglandins delayed cell clustering and further enhanced COX-2 expression. Abolishing prostaglandin production by NS-398 or indomethacin reduced cell membrane damage (as measured by lactate dehydrogenase release into the culture medium). We also identified alpha-enolase-mediated plasminogen activation as the major extracellular proteolytic executor of necrotic cell death. In contrast to inhibition of COX-2, inhibition of plasminogen activation failed to inhibit membrane damage associated with necrosis. Intracellular proteolysis, by caspases, was shown to take part in COX-2 induction. Taken together, our results indicate that cell-cell contacts induce an actively programmed necrotic process that functionally involves COX-2, a known hallmark of inflammation and cancer.
Bizik
J
J
Haartman Institute, University of Helsinki, POB 21, FIN-00014 Helsinki, Finland.
Kankuri
E
E
Ristimäki
A
A
Taïeb
A
A
Vapaatalo
H
H
Lubitz
W
W
Vaheri
A
A
D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D017209:Apoptosis / Q000235:genetics; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D002448:Cell Adhesion; D002450:Cell Communication; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002478:Cells, Cultured; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006801:Humans; D007231:Infant, Newborn; D007527:Isoenzymes / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D009336:Necrosis; D010958:Plasminogen / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011453:Prostaglandins / Q000378:metabolism; D012867:Skin / Q000166:cytology; D018874:Spheroids, Cellular / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure
D000894:Anti-Inflammatory Agents, Non-Steroidal; D061945:Caspase Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008565:Membrane Proteins; D011453:Prostaglandins; D010958:Plasminogen; D007770:L-Lactate Dehydrogenase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C496511:PTGS1 protein, human; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases; D020169:Caspases; D002118:Calcium