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TRAIL Induces Receptor-Interacting Protein 1–Dependent and Caspase-Dependent Necrosis-Like Cell Death under Acidic Extracellular Conditions

¹ Institut National de la Santé et de la Recherche Médicale UMR620, Université Rennes 1, Rennes, France and ² Institut National de la Santé et de la Recherche Médicale U517, Université Bourgogne, Dijon, France

Requests for reprints: Marie-Thérèse Dimanche-Boitrel, Institut National de la Santé et de la Recherche Médicale UMR620, Faculté de Pharmacie, 2 Av du Pr Léon Bernard, 35043 Rennes, France. Phone: 33-2-23-23-48-37; Fax: 33-2-23-23-47-94; E-mail: marie-therese.boitrel{at}rennes.inserm.fr.

Tumor necrosis factor-–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. [Cancer Res 2007;67(1):218–26]

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