TRAIL induces receptor-interacting protein 1-dependent and caspase-dependent necrosis-like cell death under acidic extracellular conditions.
Tumor necrosis factor-alpha-related apoptosis-inducing ligand (TRAIL) is a potential anticancer agent that induces apoptosis in cancer cells but not in most normal cells. How tumor physiology, particularly acidic extracellular pH (pH(e)), would modify sensitivity of cancer cells to TRAIL-induced cell death is not known. We have previously shown that cancer cells, resistant to TRAIL-induced apoptosis at physiologic pH(e) (7.4), could be sensitized to TRAIL at acidic pH(e) (6.5). However, at this acidic pH(e), cell death was necrotic. We show here that, in spite of a necrosis-like cell death morphology, caspases are activated and are necessary for TRAIL-induced cell death at acidic pH(e) in HT29 human colon cancer cells. Furthermore, we observed that, whereas receptor-interacting protein (RIP) was cleaved following TRAIL treatment at physiologic pH(e) (7.4), it was not cleaved following TRAIL treatment at acidic pH(e) (6.5). Moreover, RIP degradation by geldanamycin or decrease expression of RIP by small RNA interference transfection inhibited TRAIL-induced necrosis at acidic pH(e), showing that RIP was necessary for this necrotic cell death pathway. We also show that RIP kinase activity was essential for this cell death pathway. Altogether, we show that, under acidic pH(e) conditions, TRAIL induces a necrosis-like cell death pathway that depends both on caspases and RIP kinase activity. Thus, our data suggest for the first time that RIP-dependent necrosis might be a major death pathway in TRAIL-based therapy in solid tumors with acidic pH(e).
Meurette
Olivier
O
Institut National de la Santé et de la Recherche Médicale UMR620, Faculté de Pharmacie, Université Rennes 1, 2 Avenue du Pr Léon Bernard, 35043 Rennes, France.
Rebillard
Amélie
A
Huc
Laurence
L
Le Moigne
Gwenaëlle
G
Merino
Delphine
D
Micheau
Olivier
O
Lagadic-Gossmann
Dominique
D
Dimanche-Boitrel
Marie-Thérèse
MT
D016227:Benzoquinones / Q000494:pharmacology; D020169:Caspases / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004789:Enzyme Activation; D019073:HT29 Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D047029:Lactams, Macrocyclic / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D009336:Necrosis; D034741:RNA, Small Interfering / Q000235:genetics; D053422:Receptor-Interacting Protein Serine-Threonine Kinases / Q000378:metabolism*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D014162:Transfection
D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D016328:NF-kappa B; D034741:RNA, Small Interfering; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D053422:Receptor-Interacting Protein Serine-Threonine Kinases; D020169:Caspases; C001277:geldanamycin